Short structural variants as informative genetic markers for ALS disease risk and progression

There is considerable variability in disease progression for patients with amyotrophic lateral sclerosis (ALS) including the age of disease onset, site of disease onset, and survival time. There is growing evidence that short structural variations (SSVs) residing in frequently overlooked genomic regions can contribute to complex disease mechanisms and can explain, in part, the phenotypic variability in ALS patients. Here, we discuss SSVs recently characterized by our laboratory and how these discoveries integrate into the current literature on ALS, particularly in the context of application to future clinical trials. These markers may help to identify and differentiate patients for clinical trials that have a similar ALS disease mechanism(s), thereby reducing the impact of participant heterogeneity. As evidence accumulates for the genetic markers discovered in SQSTM1, SCAF4, and STMN2, we hope to improve the outcomes of future ALS clinical trials

Synucleinopathy in amyotrophic lateral sclerosis: A potential avenue for antisense therapeutics?

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson’s disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with “synucleinopathy disorders”. We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies

Targeted molecular therapeutics for Parkinson's Disease: A role for antisense oligonucleotides?

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by marked heterogeneity in clinical symptoms and a complex genetic background..

Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset

Neurofilament heavy (NEFH) is one of the critical proteins required for the formation of the neuronal cytoskeleton and polymorphisms in NEFH are reported as a rare cause of sporadic ALS (sALS). In the current study, a candidate tetranucleotide (TTTA) repeat variant in NEFH was selected using an in-silico short structural variant (SSV) evaluation algorithm and investigated in two cohorts of North American sALS patients, both separately and combined (Duke cohort n = 138, Coriell cohort n = 333; combined cohort n = 471), compared to a group of healthy controls from the Coriell Institute biobank (n = 496). Stratification according to site of disease onset revealed that the 9 TTTA allele was associated with reduced disease risk, specifically confined to spinal-onset sALS patients in the Duke cohort (p = 0.001). Furthermore, carriage of the 10 TTTA allele was associated with a 2.7 year later age of disease onset in the larger combined sALS cohort (p = 0.02). These results suggest that the 9 and 10 TTTA motif length may have a protective advantage for potentially lowering the risk of sALS and delaying the age of disease onset, however, these results need to be replicated in larger multicenter and multi-ethnic cohorts

Bridging the gap: Short structural variants in the genetics of anorexia nervosa

Anorexia nervosa (AN) is a devastating disorder with evidence of underexplored heritability. Twin and family studies estimate heritability (h2) to be 57%–64%, and genome-wide association studies (GWAS) reveal significant genetic correlations with psychiatric and anthropometric traits and a total of nine genome-wide significant loci. Whether significantly associated single nucleotide polymorphisms identified by GWAS are causal or tag true causal variants, remains to be elucidated. We propose a novel method for bridging this knowledge gap by fine-mapping short structural variants (SSVs) in and around GWAS-identified loci. SSV fine-mapping of loci associated with complex disorders such as schizophrenia, amyotrophic lateral sclerosis, and Alzheimer's disease has uncovered genetic risk markers, phenotypic variability between patients, new pathological mechanisms, and potential therapeutic targets. We analyze previous investigations' methods and propose utilizing an evaluation algorithm to prioritize 10 SSVs for each of the top two AN GWAS-identified loci followed by Sanger sequencing and fragment analysis via capillary electrophoresis to characterize these SSVs for case/control association studies. Success of previous SSV analyses in complex disorders and effective utilization of similar methodologies supports our proposed method. Furthermore, the structural and spatial properties of the 10 SSVs identified for each of the top two AN GWAS-associated loci, cell adhesion molecule 1 (CADM1) and NCK interacting protein with SH3 domain (NCKIPSD), are similar to previous studies. We propose SSV fine-mapping of AN-associated loci will identify causal genetic architecture. Deepening understandings of AN may lead to novel therapeutic targets and subsequently increase quality-of-life for individuals living with the illness

TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease

The translocase of outer mitochondrial membrane 40 (TOMM40) ‘523’ polymorphism has previously been associated with age of Alzheimer’s disease onset and cognitive functioning in non-pathological ageing, but has not been explored as a candidate risk marker for cognitive decline in Parkinson’s disease (PD). Therefore, this longitudinal study investigated the role of the ‘523’ variant in cognitive decline in a patient cohort from the Parkinson’s Progression Markers Initiative. As such, a group of 368 people with PD were assessed annually for cognitive performance using multiple neuropsychological protocols, and were genotyped for the TOMM40 ‘523’ variant using whole-genome sequencing data. Covariate-adjusted generalised linear mixed models were utilised to examine the relationship between TOMM40 ‘523’ allele lengths and cognitive scores, while taking into account the APOE ε genotype. Cognitive scores declined over the 5-year study period and were lower in males than in females. When accounting for APOE ε4, the TOMM40 ‘523’ variant was not robustly associated with overall cognitive performance. However, in APOE ε3/ε3 carriers, who accounted for ~60% of the whole cohort, carriage of shorter ‘523’ alleles was associated with more severe cognitive decline in both sexes, while carriage of the longer alleles in females were associated with better preservation of global cognition and a number of cognitive sub-domains, and with a delay in progression to dementia. The findings indicate that when taken in conjunction with the APOE genotype, TOMM40 ‘523’ allele length is a significant independent determinant and marker for the trajectory of cognitive decline and risk of dementia in PD

Disease-modifying effects of an SCAF4 structural variant in a predominantly SOD1 ALS cohort

Objective To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease. Methods Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with SOD1 was identified according to its theoretical effect on gene expression. An 12–18 poly-T repeat (rs573116164) within the 3′ untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (SCAF4), a gene that is adjacent to SOD1, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection. Results In a North American cohort of predominantly SOD1 fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T SCAF4 allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9–11.2; p = 4.0e-11), but also within non-SOD1 cases (n = 27; OR 5.3; 95% CI 1.9–14.5; p = 0.0014). This finding suggests genetically SOD1-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6–40.8; p = 0.014), but did not affect age at onset of disease. Conclusions The findings in this fALS cohort suggest that rs573116164 could have SOD1-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression

ALS genetics, mechanisms, and therapeutics: Where are we now?

The scientific landscape surrounding amyotrophic lateral sclerosis (ALS) continues to shift as the number of genes associated with the disease risk and pathogenesis, and the cellular processes involved, continues to grow. Despite decades of intense research and over 50 potentially causative or disease-modifying genes identified, etiology remains unexplained and treatment options remain limited for the majority of ALS patients. Various factors have contributed to the slow progress in understanding and developing therapeutics for this disease. Here, we review the genetic basis of ALS, highlighting factors that have contributed to the elusiveness of genetic heritability. The most commonly mutated ALS-linked genes are reviewed with an emphasis on disease-causing mechanisms. The cellular processes involved in ALS pathogenesis are discussed, with evidence implicating their involvement in ALS summarized. Past and present therapeutic strategies and the benefits and limitations of the model systems available to ALS researchers are discussed with future directions for research that may lead to effective treatment strategies outlined

New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective, early degeneration of motor neurons in the brain and spinal cord. Motor neurons have long axonal projections, which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability, anterograde and retrograde transport, and signaling between neurons. The formation of protein aggregates which contain cytoskeletal proteins, and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions, including ALS, Alzheimer's disease, Parkinson's disease, Huntington’s disease and Charcot-Marie-Tooth disease. Furthermore, it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked. Therefore, dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization, may be common pathways in the initial steps of neurodegeneration. Here we review and discuss known contributors, including variants in genetic loci and aberrant protein activities, which modify cytoskeletal integrity, axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases. Additionally, we explore some emerging pathways that may contribute to this disruption in ALS

Frameshift mutation in ovine muscular disease

No abstract availabl