Role of the HSP70 Co-Chaperone SIL1 in Health and Disease.

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1's function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1's functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1's NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.

Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.

The ATP/GTP-Binding Protein 1 (AGTPBP1) gene (OMIM *606830) catalyzes deglutamylation of polyglutamylated proteins, and its deficiency manifests by cerebellar ataxia and peripheral neuropathy in mice and lower motor neuron-like disease in sheep. In the mutant mice, cerebellar atrophy due to Purkinje cell degeneration is observed, likely due to increased tubulin polyglutamylation in affected brain areas. We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy. Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants in the AGTPBP1 gene. We conclude that complete loss-of-function of AGTPBP1 in humans, just like in mice and sheep, is associated with cerebellar and motor neuron disease, reminiscent of Pontocerebellar Hypoplasia Type 1 (PCH1).

[Behavioural variant of frontotemporal dementia as the presenting symptom of corticobasal degeneration]. / Variante conductual de la demencia frontotemporal como forma de presentacion de la degeneracion corticobasal.

INTRODUCTION: The behavioural variant of frontotemporal dementia is characterised by progressive social, cognitive and personality deterioration associated with several molecular pathologies of frontotemporal lobar dementia (FTLD): FTLD-tau, FTLD-TDP and FTLD-FUS. Its diagnosis requires pathological studies. CASE REPORT: A 61-year-old male, with a three-year progressive history of behavioural disorder, apathy, poor language skills, perseveration, lack of empathy, bulimia and executive dysfunction. Neuroimaging revealed right-dominant frontal cortical atrophy, and a single-photon emission tomography brain scan showed bilateral frontal hypoperfusion with thalamic and caudate involvement. Clinically, he was diagnosed with probable frontotemporal dementia, behavioural variant. On his death, his brain was donated to the Neurological Tissue Bank and the neuropathological diagnosis was corticobasal degeneration. CONCLUSIONS: Corticobasal degeneration is one of the FTLD-tau tauopathies. The 2013 diagnostic criteria for corticobasal degeneration include executive dysfunction and behavioural and personality disorders similar to those of this patient as a clinical phenotype. The anatomoclinical case presented illustrates the absence of any correlation between the clinical phenotype and the underlying neuropathological diagnosis in frontotemporal dementia, and the need to conduct a histopathological study in order to reach a definitive diagnosis.

TITLE: Variante conductual de la demencia frontotemporal como forma de presentacion de la degeneracion corticobasal.Introduccion. La variante conductual de la demencia frontotemporal se caracteriza por el deterioro progresivo de la personalidad, social y cognitivo que se asocia con diversas patologias moleculares de la degeneracion lobar frontotemporal (DLFT): DLFT-tau, DLFT-TDP y DLFT-FUS. El estudio anatomopatologico es necesario para su diagnostico. Caso clinico. Varon de 61 años, con un cuadro progresivo de tres años de evolucion de trastorno conductual, apatia, lenguaje pobre, perseveracion, falta de empatia, bulimia y disfuncion ejecutiva. En la neuroimagen se objetivo una atrofia cortical frontal de predominio derecho, y en la tomografia simple por emision de foton unico cerebral, una hipoperfusion frontoparietotemporal bilateral con afectacion de talamos y caudados. Clinicamente, se le diagnostico probable demencia frontotemporal, variante conductual. Tras su fallecimiento, se dono el cerebro al Banco de Tejidos Neurologicos y el diagnostico neuropatologico fue el de degeneracion corticobasal. Conclusiones. La degeneracion corticobasal es una de las taupatias de la DLFT-tau. Los criterios diagnosticos de degeneracion corticobasal de 2013 contemplan como fenotipo clinico la disfuncion ejecutiva, las alteraciones conductuales y de personalidad similar al de este paciente. El caso anatomoclinico presentado ilustra la falta de correlacion entre el fenotipo clinico y el diagnostico neuropatologico subyacente en la demencia frontotemporal, y la necesidad de realizar el estudio histopatologico para llegar al diagnostico definitivo.

Cerebellar degeneration and progressive ataxia associated with HIV-virus infection.

INTRODUCTION: The spectrum of neurologic disorders associated with HIV infection is very broad, resulting from direct virus invasion, opportunistic infections, malignancies and toxic effects of drugs. METHODS: Among a large cohort of ataxia patients (N = 1050) evaluated between 2008 and 2017, we detected four patients with HIV-infection who developed a pure progressive cerebellar ataxia syndrome combined with cerebellar atrophy. RESULTS: Adverse drug effects, opportunistic infections and malignancies as well as immune-reconstitution syndrome were ruled out based on history and laboratory data. The exact pathophysiological mechanisms of ataxia in HIV patients is not very clear, but seems to be immune-mediated or a direct neurotoxic virus effect leading to apoptosis of Purkinje and granular cells. CONCLUSION: HIV infection should be investigated in adult patients with undetermined sporadic progressive pure ataxia with cerebellar atrophy.

Association of Deep Gray Matter Damage With Cortical and Spinal Cord Degeneration in Primary Progressive Multiple Sclerosis.

IMPORTANCE: The investigation of cortical gray matter (GM), deep GM nuclei, and spinal cord damage in patients with primary progressive multiple sclerosis (PP-MS) provides insights into the neurodegenerative process responsible for clinical progression of MS. OBJECTIVE: To investigate the association of magnetic resonance imaging measures of cortical, deep GM, and spinal cord damage and their effect on clinical disability. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of 26 patients with PP-MS (mean age, 50.9 years; range, 31-65 years; including 14 women) and 20 healthy control participants (mean age, 51.1 years; range, 34-63 years; including 11 women) enrolled at a single US institution. Clinical disability was measured with the Expanded Disability Status Scale, 9-Hole Peg Test, and 25-Foot Walking Test. We collected data from January 1, 2012, through December 31, 2013. Data analysis was performed from January 21 to April 10, 2015. MAIN OUTCOMES AND MEASURES: Cortical lesion burden, brain and deep GM volumes, spinal cord area and volume, and scores on the Expanded Disability Status Scale (score range, 0 to 10; higher scores indicate greater disability), 9-Hole Peg Test (measured in seconds; longer performance time indicates greater disability), and 25-Foot Walking Test (test covers 7.5 m; measured in seconds; longer performance time indicates greater disability). RESULTS: The 26 patients with PP-MS showed significantly smaller mean (SD) brain and spinal cord volumes than the 20 control group patients (normalized brain volume, 1377.81 [65.48] vs 1434.06 [53.67] cm3 [P = .003]; normalized white matter volume, 650.61 [46.38] vs 676.75 [37.02] cm3 [P = .045]; normalized gray matter volume, 727.20 [40.74] vs 757.31 [38.95] cm3 [P = .02]; normalized neocortical volume, 567.88 [85.55] vs 645.00 [42.84] cm3 [P = .001]; normalized spinal cord volume for C2-C5, 72.71 [7.89] vs 82.70 [7.83] mm3 [P < .001]; and normalized spinal cord volume for C2-C3, 64.86 [7.78] vs 72.26 [7.79] mm3 [P =.002]). The amount of damage in deep GM structures, especially with respect to the thalamus, was correlated with the number and volume of cortical lesions (mean [SD] thalamus volume, 8.89 [1.10] cm3; cortical lesion number, 12.6 [11.7]; cortical lesion volume, 0.65 [0.58] cm3; r = -0.52; P < .01). Thalamic atrophy also showed an association with cortical lesion count in the frontal cortex (mean [SD] thalamus volume, 8.89 [1.1] cm3; cortical lesion count in the frontal lobe, 5.0 [5.7]; r = -0.60; P < .01). No association was identified between magnetic resonance imaging measures of the brain and spinal cord damage. CONCLUSIONS AND RELEVANCE: In this study, the neurodegenerative process occurring in PP-MS appeared to spread across connected structures in the brain while proceeding independently in the spinal cord. These results support the relevance of anatomical connectivity for the propagation of MS damage in the PP phenotype.

Early-stage Alcoholic Cerebellar Degeneration: Diagnostic Imaging Clues

No abstract available.

Canine hereditary ataxia in old english sheepdogs and gordon setters is associated with a defect in the autophagy gene encoding RAB24.

Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.

JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment.

Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging.

Physiotherapy in degenerative cerebellar ataxias: utilisation, patient satisfaction, and professional expertise.

Physiotherapy plays an important role in the management of patients with degenerative cerebellar ataxias. However, our insight in the quantity and quality of physiotherapy prescription in this group of patients is incomplete. The purposes of this study were to investigate the utilization of physiotherapy and patient satisfaction in patients with degenerative ataxias in The Netherlands and to examine the level of expertise and needs of physiotherapists treating ataxia patients. Questionnaires were sent to members of the Dutch association for patients with degenerative cerebellar ataxias (n = 532). In addition, 181 questionnaires were sent to the physiotherapists who had recently treated the patients who responded. Eventually, 317 questionnaires from patients (60 %) and 114 questionnaires from physiotherapists (63 %) could be used for further analysis. Sixty-four percent of the patients were currently treated by a physiotherapist. Their median treatment duration was 5 years. Nineteen percent of the patients had never been referred, often despite the presence of limitations in daily activities. On the other hand, some participants without reported limitations had received physiotherapy. In general, participants were satisfied with their physiotherapist. The most reported treatment goals were improvement or maintenance of balance, general physical condition, and mobility. Physiotherapists reported lack of ataxia-specific expertise and expressed the need for education and evidence-based guidelines. Referral to and use of physiotherapy in patients with degenerative cerebellar ataxia in The Netherlands are currently inconsistent and not in agreement with the little scientific evidence available. Referral rates are high, but referrals and actual necessity are discrepant; treatment duration is long; and ataxia-specific expertise among physiotherapists is insufficient. Evidence-based recommendations and specific training of physiotherapists are needed.

A practical approach to late-onset cerebellar ataxia: putting the disorder with lack of order into order.

The clinical management of cerebellar ataxia is challenging, mainly because ataxia is a symptom of many neurological diseases. Many types of ataxia disorders are genetic and some are extremely rare. Here, the authors suggest a diagnostic approach to ataxia developed around a case of sporadic, late-onset, slowly progressive ataxia. Clinical information such as age of onset, rate of progression, family history and certain non-cerebellar features can narrow the differential diagnosis. Brain MRI is almost obligatory and may reveal valuable diagnostic clues. Having ruled out structural lesions, the two other most common diagnoses are inflammatory and degenerative (including genetic) disorders. Although only a minority of underlying diseases are treatable, there are still many options for supportive care.

Mapping cerebellar degeneration in HIV/AIDS.

Progressive brain atrophy in HIV/AIDS is associated with impaired psychomotor performance, perhaps partly reflecting cerebellar degeneration; yet little is known about how HIV/AIDS affects the cerebellum. We visualized the three-dimensional profile of atrophy in 19 HIV-positive patients (age: 42.9+/-8.3 years) versus 15 healthy controls (age: 38.5+/-12.0 years). We localized consistent patterns of subregional atrophy with an image analysis method that automatically deforms each patient's scan, in three dimensions, to match a reference image. Atrophy was greatest in the posterior cerebellar vermis (14.9% deficit) and correlated with depression severity (P=0.009, corrected), but not with dementia, alcohol/substance abuse, CD4+T-cell counts, or viral load. Profound cerebellar deficits in HIV/AIDS (P=0.007, corrected) were associated with depression, suggesting a surrogate disease marker for antiretroviral trials.