Tau filaments with the Alzheimer fold in cases with MAPT mutations V337M and R406W.

Frontotemporal dementia (FTD) and Alzheimer's disease are the most common forms of early-onset dementia. Dominantly inherited mutations in MAPT , the microtubule-associated protein tau gene, cause FTD and parkinsonism linked to chromosome 17 (FTDP-17). Individuals with FTDP-17 develop abundant filamentous tau inclusions in brain cells. Here we used electron cryo-microscopy to determine the structures of tau filaments from the brains of individuals with MAPT mutations V337M and R406W. Both mutations gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified a new assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau(297-391) with mutation V337M had the Alzheimer fold and showed an increased rate of assembly.

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.

TREM2 variants that cause early dementia and increase Alzheimer's disease risk affect gene splicing.

Loss-of-function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In the homozygous state, they cause severe pathologies with early onset dementia, such as Nasu-Hakola disease (NHD) and behavioral variants of frontotemporal dementia (FTD), whereas heterozygous variants increase the risk of late-onset Alzheimer's disease (AD) and FTD. For over half of TREM2 variants found in families with recessive early onset dementia, the defect occurs at the transcript level via premature termination codons or aberrant splicing. The remaining variants are missense alterations thought to affect the protein; however, the underlying pathogenic mechanism is less clear. In this work, we tested whether these disease-associated TREM2 variants contribute to the pathology via altered splicing. Variants scored by SpliceAI algorithm were tested by a full-size TREM2 splicing reporter assay in different cell lines. The effect of variants was quantified by qRT-/RT-PCR and western blots. Nanostring nCounter was used to measure TREM2 RNA in the brains of NHD patients who carried spliceogenic variants. Exon skipping events were analyzed from brain RNA-Seq datasets available through the Accelerating Medicines Partnership for Alzheimer's Disease Consortium (AMP-AD). We found that for some NHD and early onset FTD-causing variants, splicing defects were the primary cause (D134G) or likely contributor to pathogenicity (V126G and K186N). Similar but milder effects on splicing of exons 2 and 3 were demonstrated for A130V, L133L and R136W enriched in patients with dementia. Moreover, the two most frequent missense variants associated with AD/FTD risk in European and African ancestries (R62H, 1% in Caucasians, and T96K, 12% in Africans) had splicing defects via excessive skipping of exon 2 and overproduction of a potentially antagonistic TREM2 protein isoform. The effect of R62H on exon 2 skipping was confirmed in three independent brain RNA-seq datasets. Our findings revealed an unanticipated complexity of pathogenic variation in TREM2, in which effects on post-transcriptional gene regulation and protein function often coexist. This necessitates the inclusion of computational and experimental analyses of splicing and mRNA processing for a better understanding of genetic variation in disease.

NOTCH3 C201R variant causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) that can be confused with early-onset Alzheimer's disease.

BACKGROUND: NOTCH3 is the causative gene for autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) which is associated with both stroke and dementia. When CADASIL presents primarily as dementia it can be difficult to distinguish from Alzheimer's disease (AD) at both the clinical and neuropathological levels. METHODS: We performed exome sequencing of several affected individuals from a large family affected with AD. PCR amplification and direct Sanger sequencing were used to verify variants detected by exome analysis and to screen family members at-risk to carry those variants. Neuropathologic brain evaluation by immunohistochemistry and MRI were performed for the carriers of the NOTCH3 variant. RESULTS: In a three-generation family with AD, we found a c.601 T > C p.Cys201Arg variant in the NOTCH3 gene that caused clinical and neuropathological manifestations of CADASIL. These features included earlier onset of dementia accompanied by behavioral abnormalities in the father and son and white matter abnormalities in the asymptomatic grandson. The family is one branch of a large pedigree studied by the Alzheimer's Disease Sequencing Project (ADSP). As part of the ADSP linkage analysis and whole genome sequencing endeavor, an ABCA1 variant, p.Ala937Val, was previously found associated with AD in this pedigree. CONCLUSIONS: Our findings, together with other reported pathogenic missense variants of the C201 codon in NOTCH3, support the role of cysteine 201 as a mutation hotspot for CADASIL and highlight the genetic complexity both clinically and pathologically of AD and related dementia.

Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease.

Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and alternative splicing of these two genes has been implicated in both familial and sporadic Alzheimer's disease. Here, we leveraged targeted isoform-sequencing to characterize thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic Alzheimer's disease, familial Alzheimer's disease (carrying PSEN1 and PSEN2 variants), and controls. Our results reveal alternative splicing patterns of PSEN2 specific to sporadic Alzheimer's disease, including a human-specific cryptic exon present in intron 9 of PSEN2 as well as a 77 bp intron retention product before exon 6 that are both significantly elevated in sporadic Alzheimer's disease samples, alongside a significantly lower percentage of canonical full-length PSEN2 transcripts versus familial Alzheimer's disease samples and controls. Both alternatively spliced products are predicted to generate a prematurely truncated PSEN2 protein and were corroborated in an independent cerebellum RNA-sequencing dataset. In addition, our data in PSEN variant carriers is consistent with the hypothesis that PSEN1 and PSEN2 variants need to produce full-length but variant proteins to contribute to the onset of Alzheimer's disease, although intriguingly there were far fewer full-length transcripts carrying pathogenic alleles versus wild-type alleles in PSEN2 variant carriers. Finally, we identify frequent RNA editing at Alu elements present in an extended 3' untranslated region in PSEN2. Overall, this work expands the understanding of PSEN1 and PSEN2 variants in Alzheimer's disease, shows that transcript differences in PSEN2 may play a role in sporadic Alzheimer's disease, and suggests novel mechanisms of Alzheimer's disease pathogenesis.

Aß and tau prions feature in the neuropathogenesis of Down syndrome.

Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer's disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aß and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aß and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aß and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aß and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aß and tau prions increased with age. In contrast to DS brains, the levels of Aß and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.

Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Reduced gene dosage is a common mechanism of neuropathologies caused by ATP6AP2 splicing mutations.

BACKGROUND: Mutations that alter splicing of X-linked ATP6AP2 cause a spectrum of neurodevelopmental and neurodegenerative pathologies including parkinsonism in affected males. All previously reported splicing mutations increase the level of a minor isoform with skipped exon 4 (Δe4) that encodes a functionally deficient protein. OBJECTIVES: We investigated the pathogenic mechanism of a novel c.168+6T>A variant reported in a family with X-linked intellectual disability, epilepsy, and parkinsonism. We also analyzed ATP6AP2 splicing defects in brains of carriers of a c.345C>T variant associated with X-linked spasticity and parkinsonism. METHODS: We generated induced pluripotent stem cells from patients with c.168+6T>A, reprogrammed them to neural progenitor cells and analyzed them by RNA-Seq and qRT-PCR. We also quantified ATP6AP2 isoforms in the brains of c.345C>T carriers by Nanostring nCounter. RESULTS: The c.168+6T>A increased skipping of ATP6AP2 exon 2 and usage of cryptic intronic donor splice sites. This results in out-of-frame splicing products and a reciprocal 50% reduction in functional full-length ATP6AP2 transcripts. Neural progenitors of patients with c.168+6T>A exhibited downregulated neural development gene networks. Analysis of blood transcriptomes of c.168+6T>A carriers identified potential biomarkers of ATP6AP2 deficiency in non-neural tissues. The c.345C>T variant increased exon 4 skipping with concomitant decrease of full length ATP6AP2 in brains of carriers. CONCLUSION: A common pathogenic consequence of splicing mutations affecting inclusion of different ATP6AP2 exons is reduction of the functional full-length transcript. The exacerbated ATP6AP2 splicing defect in brains of c.345C>T carriers is consistent with their CNS-restricted clinical presentations.

Progress in Amyotrophic Lateral Sclerosis Gene Discovery: Reflecting on Classic Approaches and Leveraging Emerging Technologies.

Amyotrophic lateral sclerosis (ALS) is the most prominent motor neuron disease in humans. Its etiology consists of progressive motor neuron degeneration resulting in a rapid decline in motor function starting in the limbs or bulbar muscles and eventually fatally impairing central organs most typically resulting in loss of respiration. Pathogenic variants in 4 main genes, SOD1, TARDBP, FUS, and C9orf72, have been well characterized as causative for more than a decade now. However, these only account for a small fraction of all ALS cases. In this review, we highlight many additional variants that appear to be causative or confer increased risk for ALS, and we reflect on the technologies that have led to these discoveries. Next, we call attention to new challenges and opportunities for ALS and suggest next steps to increase our understanding of ALS genetics. Finally, we conclude with a synopsis of gene therapy paradigms and how increased understanding of ALS genetics can lead us to developing effective treatments. Ultimately, a consolidated update of the field can provide a launching point for researchers and clinicians to improve our search for ALS-related genes, defining pathogenic mechanisms, form diagnostics, and develop therapies.

TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans.

Although amyloid ß (Aß) and tau aggregates define the neuropathology of Alzheimer's disease (AD), TDP-43 has recently emerged as a co-morbid pathology in more than half of patients with AD. Individuals with concomitant Aß, tau and TDP-43 pathology experience accelerated cognitive decline and worsened brain atrophy, but the molecular mechanisms of TDP-43 neurotoxicity in AD are unknown. Synergistic interactions among Aß, tau and TDP-43 may be responsible for worsened disease outcomes. To study the biology underlying this process, we have developed new models of protein co-morbidity using the simple animal Caenorhabditis elegans. We demonstrate that TDP-43 specifically enhances tau but not Aß neurotoxicity, resulting in neuronal dysfunction, pathological tau accumulation and selective neurodegeneration. Furthermore, we find that synergism between tau and TDP-43 is rescued by loss-of-function of the robust tau modifier sut-2. Our results implicate enhanced tau neurotoxicity as the primary driver underlying worsened clinical and neuropathological phenotypes in AD with TDP-43 pathology, and identify cell-type specific sensitivities to co-morbid tau and TDP-43. Determining the relationship between co-morbid TDP-43 and tau is crucial to understand, and ultimately treat, mixed pathology AD.

Familial Idiopathic Basal Ganglia Calcification: A Father-Son Dyad Demonstrate Heterogeneity of Presentation and Disease Progression.

OBJECTIVE: Familial idiopathic basal ganglia calcification (FIBGC) is a rare, heritable disease characterized by calcium deposition in the basal ganglia and other brain regions. Clinical presentations are diverse, featuring an array of neurologic, psychiatric, and/or cognitive symptoms. This dyad report presents neurogenetic, neuroimaging, neurological, and serial neuropsychological data from a father (S1) and son (S2) with FIBGC. METHOD/RESULTS: The SLC20A2 genetic mutation c.1828-1831delTCCC was identified for each patient, both of whom evidenced similar patterns of brain calcification mainly in the basal ganglia and cerebellum on neuroimaging. S1's onset was in his late 60s with primary motor abnormalities followed by cognitive decline; S2's younger onset (late 30s) was characterized by predominant psychiatric symptoms and mild cognitive changes. Our unique, detailed longitudinal study revealed that both subjects demonstrated largely stable performance across most neuropsychological domains assessed. CONCLUSIONS: The subjects' differences in presentation demonstrate the variable expressivity in FIBGC even with the same pathogenic variant within a single family. Distinct phenotypes may be associated with age of onset even in persons with the same mutation, consistent with past research. Disease progression may feature an initial period of notable change from baseline followed by relative stability, as seen both on imaging and neuropsychological evaluation.

Spinal cord-predominant neuropathology in an adult-onset case of POLR3A-related spastic ataxia.

Biallelic mutations in POLR3A have been associated with childhood-onset hypomyelinating leukodystrophies and adolescent-to-adult-onset spastic ataxia, the latter of which has been linked to the intronic variant c.1909 + 22G>A. We report a case of adult-onset spastic ataxia in a 75-year-old man, being a compound heterozygous carrier of this variant, whose brain and spinal cord were for the first time investigated by neuropathological examination. We describe prominent degeneration of the posterior columns, spinocerebellar tracts, and anterior corticospinal tracts of the spinal cord in a pattern resembling Friedreich's ataxia, with a notable lack of significant white matter pathology throughout the brain, in marked contrast with childhood-onset cases. Immunohistochemical examination for the POLR3A protein demonstrated no apparent differences in localization or staining intensity between the proband and an age-matched control subject. We demonstrate the clinicopathologic description of POLR3A-related neurodegenerative disease and also mention the differential diagnosis of the childhood-onset hypomyelinating leukodystrophy and late-onset spastic ataxia phenotypes.

C9orf72 Hexanucleotide Repeat in Huntington-Like Patients: Systematic Review and Meta-Analysis.

Introduction: Patients with Huntington-Like disorders (HLD) comprise a variety of allelic disorders sharing a Huntington phenotype. The hexanucleotide repeat expansion of the C9orf72 gene could explain part of the HLD etiology. We aimed to conduct a systematic review and meta-analysis looking for the frequency of the hexanucleotide repeat expansion of the C9orf72 gene in HLD patients. Methods: The protocol was registered on the International Prospective Register of Systematic Reviews database (PROSPERO) (registration number: CRD42018105465). The search was carried out in Medline, Scopus, Web of Science, and Embase in April 2018, and updated in July 2020. Observational studies reporting patients with HLD carrying the hexanucleotide repeat expansion in the C9orf72 gene were selected and reviewed; this process was duplicated. The cutoff threshold for considering the hexanucleotide expansion as a pathogenic variant was equal to or >30 G4C2 repeats. Cases with intermediate alleles with 20-29 repeat are also analyzed. Pooled frequency and 95% CI were calculated using random-effects models. Results: Nine out of 219 studies were selected, reporting 1,123 affected individuals with HLD. Among them, 18 individuals carried C9orf72 expansion, representing 1% (95% CI: 0-2%, I 2 = 0%) of the pooled frequency. Seven selected studies came from European centers, one was reported at a US center, and one came from a South-African center. We identified five individuals carrying intermediate alleles representing 3% (95% CI: 0-14%, I 2 = 78.5%). Conclusions: The frequency of C9orf72 unstable hexanucleotide repeat expansion in HLD patients is very low. Further studies with more accurate clinical data and from different ethnic backgrounds are needed to confirm this observation.

Adult onset pan-neuronal human tau tubulin kinase 1 expression causes severe cerebellar neurodegeneration in mice.

The kinase TTBK1 is predominantly expressed in the central nervous system and has been implicated in neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis through its ability to phosphorylate the proteins tau and TDP-43. Mutations in the closely related gene TTBK2 cause spinocerebellar ataxia, type 11. However, it remains unknown whether altered TTBK1 activity alone can drive neurodegeneration. In order to characterize the consequences of neuronal TTBK1 upregulation in adult brains, we have generated a transgenic mouse model with inducible pan-neuronal expression of human TTBK1. We find that these inducible TTBK1 transgenic mice (iTTBK1 Tg) exhibit motor and cognitive phenotypes, including decreased grip strength, hyperactivity, limb-clasping, and spatial memory impairment. These behavioral phenotypes occur in conjunction with progressive weight loss, neuroinflammation, and severe cerebellar degeneration with Purkinje neuron loss. Phenotype onset begins weeks after TTBK1 induction, culminating in average mortality around 7 weeks post induction. The iTTBK1 Tg animals lack any obvious accumulation of pathological tau or TDP-43, indicating that TTBK1 expression drives neurodegeneration in the absence of detectable pathological protein deposition. In exploring TTBK1 functions, we identified the autophagy related protein GABARAP to be a novel interacting partner of TTBK1 and show that GABARAP protein levels increase in the brain following induction of TTBK1. These iTTBK1 Tg mice exhibit phenotypes reminiscent of spinocerebellar ataxia, and represent a new model of cerebellar neurodegeneration.

Triggering Receptor Expressed on Myeloid Cell 2 R47H Exacerbates Immune Response in Alzheimer's Disease Brain.

The R47H variant in the microglial triggering receptor expressed on myeloid cell 2 (TREM2) receptor is a strong risk factor for Alzheimer's disease (AD). To characterize processes affected by R47H, we performed an integrative network analysis of genes expressed in brains of AD patients with R47H, sporadic AD without the variant, and patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), systemic disease with early-onset dementia caused by loss-of-function mutations in TREM2 or its adaptor TYRO protein tyrosine kinase-binding protein (TYROBP). Although sporadic AD had few perturbed microglial and immune genes, TREM2 R47H AD demonstrated upregulation of interferon type I response and pro-inflammatory cytokines accompanied by induction of NKG2D stress ligands. In contrast, PLOSL had distinct sets of highly perturbed immune and microglial genes that included inflammatory mediators, immune signaling, cell adhesion, and phagocytosis. TREM2 knockout (KO) in THP1, a human myeloid cell line that constitutively expresses the TREM2- TYROBP receptor, inhibited response to the viral RNA mimetic poly(I:C) and phagocytosis of amyloid-beta oligomers; overexpression of ectopic TREM2 restored these functions. Compared with wild-type protein, R47H TREM2 had a higher stimulatory effect on the interferon type I response signature. Our findings point to a role of the TREM2 receptor in the control of the interferon type I response in myeloid cells and provide insight regarding the contribution of R47H TREM2 to AD pathology.

Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1.

The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.

Mutations in the SIGMAR1 gene cause a distal hereditary motor neuropathy phenotype mimicking ALS: Report of two novel variants.

Distal hereditary motor neuropathy (dHMN) is an inherited neuromuscular disease characterized by symmetric distal weakness and atrophy without sensory changes. There are about thirty known genes associated with dHMN, but together they explain only about a third of cases. Mutations in the sigma non-opioid intracellular receptor 1 gene (SIGMAR1) has been linked to autosomal recessive dHMN with pyramidal signs in several families. This phenotype can mimic amyotrophic lateral sclerosis (ALS). We report a 39-year-old man who was referred to our ALS clinic with distal motor weakness and hyperreflexia. Whole exome sequencing identified two novel variants in the SIGMAR1 gene in the proband. Targeted Sanger sequencing of asymptomatic family members confirmed that each carried one of these two variants. Our findings expand the number of known SIGMAR1 pathogenic variants associated with dHMN, which should be clinically distinguished from ALS.

Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization.

OBJECTIVE: To identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant STUB1-related ataxia and investigate the effects of pathogenic variants on STUB1 localization. METHODS: Clinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families. RESULTS: Mutations in STUB1 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in STUB1 (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors. CONCLUSIONS: This study confirms a dominant inheritance pattern in STUB1-ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.

Hyperphosphorylated Tau, Increased Adenylate Cyclase 5 (ADCY5) Immunoreactivity, but No Neuronal Loss in ADCY5-Dyskinesia.

BACKGROUND: Adenylate cyclase 5 (ADCY5)-related dyskinesia is a childhood-onset movement disorder. Manifestations vary in frequency and severity and may include chorea, tremor, dystonia, facial twitches, myoclonus, axial hypotonia, and limb hypertonia. Psychosis is likely part of the broader spectrum. ADCY5 is widely expressed in the brain, especially in the striatum. Previous reports of brain autopsies of 2 subjects with likely ADCY5-dyskinesia were limited by the absence of a molecular diagnosis. In 1 case, normal gross pathology was reported. In the other case, ADCY5 expression was not examined and neuropathological findings were confounded by age and comorbidities. OBJECTIVES: To examine ADCY5 expression and neuropathological changes in ADCY5-dyskinesia. METHODS: An extensive brain autopsy, including immunohistochemical analyses with antibodies to paired helical filament tau, α-synuclein, amyloid-ß, microtubule-associated protein 2, and ADCY5, was performed. RESULTS: The patient, with a p.M1029K ADCY5 variant, had severe dyskinesias from early childhood, later recurrent episodes of psychosis, and died at age 46. Gross pathology was unremarkable, but we detected increased immunoreactivity for ADCY5 in neurons in multiple brain regions. Despite no history of brain trauma to suggest chronic traumatic encephalopathy, we found tau deposits in the deep cortical sulci, midbrain, and hippocampus with minimal amyloid pathology and no Lewy bodies. CONCLUSIONS: We present the first brain autopsy findings in a molecularly proven case of ADCY5-dyskinesia, showing increased ADCY5 immunoreactivity in neurons and evidence of tau deposition. Additional patients will need to be studied to determine whether increased immunoreactivity for ADCY5 is a signature for ADCY5-dyskinesia and whether this disease has a tauopathy component.