A Meta-Analysis of α-Synuclein Multiplication in Familial Parkinsonism

Book, Adam A.; Guella, Ilaria; Candido, Tara; Brice, Alexis; Hattori, Nobutaka; Jeon, Beomseok; Farrer, Matthew J.

doi:10.3389/fneur.2018.01021

Cited by 97 publications

(98 citation statements)

References 38 publications

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“…It is important to state that we filtered and assessed all 1.2-fold expression dysregulations with nominal significance, if they were components of a pathway that showed enrichment after correction for multiple testing. The reasoning behind the screening of so subtle changes comes from research into Parkinson’s disease (PD), where 2-fold dosage increase of the disease protein alpha-synuclein was shown to trigger disease onset at ages of 30 years, 1.5-fold increase causes onset around 50 years, and 1.3-fold increase starts disease after 70 years of age [19, 34, 191]. The survey of 1.2-fold global transcriptome dysregulations in a PD mouse model correctly discovered neuroinflammatory changes as initial molecular pathology, which were later found to be crucial for a successful rescue [193, 205].…”

Section: Resultsmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology.Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies. Introduction:Within the dynamic research field into neurodegenerative disorders, the rare monogenic variant SCA2 (Spinocerebellar Ataxia type 2) gained much attention over the past decade, since its pathogenesis is intertwined with the motor neuron diseases ALS/FTLD (Amyotrophic Lateral Sclerosis / Fronto-Temporal Lobar Dementia) and with extrapyramidal syndromes such as Parkinson/PSP (Progressive Supranuclear Palsy). Particularly in the past year, it received massive interest since antisense-oligonucleotides were shown to effectively prevent the disease in mouse models, with clinical trials now being imminent. Still, there is an urgent unmet need to define the molecular events of pathogenesis and to identify biomarkers of progression in SCA2 patients, which reflect therapeutic benefits much more rapidly than clinical rating scales, brain imaging volumetry or neurophysiology measures.SCA2 was first described as separate entity in Indian patients, based on the characteristic early slowing of eye saccadic movements [222]. A molecularly homogeneous founder population of ~1,000 patients in...

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Section: Resultsmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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“…As a positive control for aCGH, we also included a sample from a known subject with an SNCA triplication. [38][39][40][41] We also interrogated a Baylor Genetics diagnostic laboratory sample including 12,922 clinical referral samples for aCGH from peripheral blood. 42 This analysis of aggregate clinical genomic data was also approved by the BCM Institutional Review Board.…”

Section: Subjectsmentioning

confidence: 99%

“…64,65 As a positive control for our aCGH analysis, we also included a known SNCA triplication sample from the index family in which SNCA locus multiplication was first discovered as a cause for PD. [38][39][40][41] Breakpoint sequencing revealed that this copy number alteration is a 1.7 Mb complex genomic rearrangement ( Figure 1B), consisting of a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP). This finding confirms and extends prior investigation of this particular structural variant 66 and is also consistent with a likely replication-based mechanism for CNV formation.…”

Section: Copy Number Variantsmentioning

confidence: 99%

Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

Robak

Du²,

Yuan³

et al. 2019

Preprint

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Background: Parkinson's disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors.We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors. Methods:We performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. Results:Using exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). Two subjects were each double heterozygotes for variants in GBA and LRRK2.Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. Conclusions:Integrated exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

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“…Notably, mouse lethality observed from the brain‐specific double knockout of both GAK ( DNAJC26 ) and auxilin ( DNAJC6 ) can be rescued by introducing a 3’‐fragment of the complimentary DNA (cDNA) sequence that retains both clathrin‐binding and J domains . Perhaps most remarkably, neurodegeneration in the DnaJ Heat Shock Protein Family (Hsp40) Member C5 ( DNAJC5 ) null mouse is rescued by α‐synuclein overexpression, yet α‐synuclein multiplication mutations cause familial parkinsonism . Several more genes that directly encode lysosomal proteins have been implicated in familial/atypical parkinsonism including ATPase Cation Transporting 13A2 ( ATP13A2 ), ATPase H+ Transporting Accessory Protein 2 ( ATP6AP2 ), Glucosylceramidase Beta ( GBA ), Phospholipase A2 Group VI ( PLA2G6 ), RAB39B and Scavenger Receptor Class B Member 2 ( SCARB2 ) .…”

mentioning

confidence: 99%

“…13 Perhaps most remarkably, neurodegeneration in the DnaJ Heat Shock Protein Family (Hsp40) Member C5 (DNAJC5) null mouse is rescued by α-synuclein overexpression, 14 yet α-synuclein multiplication mutations cause familial parkinsonism. 15 Several more genes that directly encode lysosomal proteins have been implicated in familial/atypical parkinsonism including ATPase Cation Transporting 13A2 (ATP13A2), ATPase H+ Transporting Accessory Protein 2 (ATP6AP2), Glucosylceramidase Beta (GBA), Phospholipase A2 Group VI (PLA2G6), RAB39B and Scavenger Receptor Class B Member 2 (SCARB2). 16 However, compromised lysosomal-autophagic processing may contribute to the inclusion pathology observed in many neurodegenerative disorders, not only the selective vulnerability of midbrain dopaminergic neurons.…”

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confidence: 99%