SUMOtherapeutics for Ischemic Stroke.

The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance.

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites 1 . Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus , provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage 2 . Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo . Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

Somatic SNCA Copy Number Variants in Multiple System Atrophy are Related to Pathology and Inclusions.

BACKGROUND: Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains. OBJECTIVE: The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions. METHODS: We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP). RESULTS: We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions. CONCLUSIONS: The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer's disease mouse model and risk loci carriers.

Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of the importance of metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late-onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics, and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these data sets using gene ontology, transcription factor, pathway, and cell-type enrichment analyses. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic data set derived from cortical tissue of ABCA-7 null mice, a mouse model of one of the genes associated with late-onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and genes associated with AD risk. We found 203 DE transcripts, 164 DE proteins, and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetic metabolic pathways were significantly over-represented across the AD multi-omics data sets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modeled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms-metabolite associations, of which 70% corresponded to lipid classes. These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabolic alterations.

Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson's disease-associated GBA gene.

GBA variants carriers are at increased risk of Parkinson's disease (PD) and Lewy body dementia (LBD). The presence of pseudogene GBAP1 predisposes to structural variants, complicating genetic analysis. We present two methods to resolve recombinant alleles and other variants in GBA: Gauchian, a tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore sequencing after PCR enrichment. Both methods were concordant for 42 samples carrying a range of recombinants and GBAP1-related mutations, and Gauchian outperformed the GATK Best Practices pipeline. Applying Gauchian to sequencing of over 10,000 individuals shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls. Gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects more GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA analysis in these patients.

Necrosis and Brain Invasion Predict Radio-Resistance and Tumor Recurrence in Atypical Meningioma: A Retrospective Cohort Study.

BACKGROUND: Meningiomas are the most common tumors occurring in the central nervous system, with variable recurrence rates depending on World Health Organization grading. Atypical (Grade II) meningioma has a higher rate of recurrence than benign (Grade I) meningioma. The efficacy of adjuvant radiotherapy (RT) to improve tumor control has been questioned. OBJECTIVE: To investigate clinical and histopathological predictors of tumor recurrence and radio-resistance in atypical meningiomas. METHODS: This cohort study retrospectively reviewed all patients in St. Michael's Hospital CNS tumor patient database who underwent surgical resection of a Grade II meningioma from 1995 to 2015. Cases with neurofibromatosis type II, multiple satellite tumors, spinal cord meningioma, radiation-induced meningioma, and perioperative death were excluded. Patient demographics, neuropathological diagnosis, tumor location, extent of resection, radiation therapy, and time to recurrence or progression were recorded. Cox univariate regression and Kaplan-Meier survival analysis were employed to identify risk factors for recurrence and radio-resistance. RESULTS: Among 181 patients, the combination of necrosis and brain invasion was associated with an increased recurrence risk (hazard ratio [HR] = 4.560, P = .001) and the lowest progression-free survival (PFS) relative to other pathological predictors. This trend was maintained after gross total resection (GTR, P = .001). RT was associated with decreased PFS (P = .001), even in patients who received GTR (P = .001). CONCLUSION: The combination of necrosis and brain invasion is a strong predictor of tumor recurrence and radio-resistance in meningioma, regardless of EOR or adjuvant RT. Our findings question the sensibility of brain invasion as an absolute criterion for Grade II status.

APOE ɛ4/ɛ4 Is Associated with Aberrant Motor Behavior Through Both Lewy Body and Cerebral Amyloid Angiopathy Pathology in High Alzheimer's Disease Pathological Load.

BACKGROUND: Aberrant motor behavior (AMB) is a neuropsychiatric symptom (NPS) prevalent in Alzheimer's disease (AD), known to cause great distress to both patients and caregivers. Apolipoprotein E4 (APOE4) is the most important genetic predictor of AD, and it has been associated with high NPS prevalence. OBJECTIVE: To investigate the neuropathological substrates and risk factors associated with AMB in AD patients. METHODS: Cases with Braak stage I-II and CERAD 0-1 were classified as Low AD (LAD), while Braak stage III-IV and CERAD 2 were grouped as Intermediate AD (IAD). Cases with Braak stage V-VI and CERAD 3 were classified as High AD (HAD) in accordance with NIA-Reagan criteria. All cases were stratified by APOE genotype, yielding No ɛ4 & ɛ4 and ɛ4/ɛ4 groups depending on ɛ4 copy number within APOE. Presence of AMB was assessed using NPI-Q. RESULTS AND CONCLUSION: AMB increased in parallel with CERAD and Braak & Braak scores. Hypercholesterolemia, but no other cardiovascular risk factors, was associated with AMB in HAD. AMB prevalence in HAD was significantly increased in the presence of two APOEɛ4 alleles as compared to No ɛ4 & ɛ4. The relationship between homozygous APOE4 and AMB was strongly associated with the presence of both Lewy bodies and cerebral amyloid angiopathy pathologies in both sexes.