Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.

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High content live profiling reveals concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

10.1101/2020.04.15.040394 ◽

2020 ◽

Cited By ~ 1

Author(s):

Arun Pal ◽

Benedikt Kretner ◽

Masin Abo-Rady ◽

Hannes Glaß ◽

Marcel Naumann ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Loss Of Function ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

Organelle Motility ◽

Gain And Loss ◽

Induced Pluripotent ◽

Dna Strand ◽

Axonal Trafficking ◽

Lateral Sclerosis

AbstractIntronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS), a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOF) through DPRs versus loss of C9ORF72 functions (LOF). Through multiparametric HC live profiling in spinal MNs from induced pluripotent stem cells (iPSCs) and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA strand breaks (DSBs), DPRs and apoptosis. We show that both GOF and LOF were necessary to yield the overall C9ORF72 pathology. Finally, C9ORF72 LOF was sufficient – albeit to a smaller extent – to induce proximal axonal trafficking deficits and increased DSBs.Single sentence summaryPathogenesis in C9ORF72 ALS shows a distinct spatiotemporal axonal organelle trafficking impairment caused by gain and loss of function mechanisms.

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The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

Cells ◽

10.3390/cells10081865 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1865

Author(s):

Nica Borgese ◽

Nicola Iacomino ◽

Sara Francesca Colombo ◽

Francesca Navone

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Adaptor Proteins ◽

Loss Of Function ◽

Membrane Contact Sites ◽

Physiological Processes ◽

Main Driver ◽

Single Allele ◽

Induced Pluripotent ◽

Lateral Sclerosis

The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.

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Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions inC9orf72

JAMA Neurology ◽

10.1001/jamaneurol.2013.5762 ◽

2014 ◽

Vol 71 (6) ◽

pp. 771 ◽

Cited By ~ 40

Author(s):

Jill S. Goldman ◽

Catarina Quinzii ◽

Jane Dunning-Broadbent ◽

Cheryl Waters ◽

Hiroshi Mitsumoto ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Multiple System Atrophy ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

Lateral Sclerosis

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Analysis of C9orf72 hexanucleotide repeat expansions in SOD1 negative patients with amyotrophic lateral sclerosis

Pathology ◽

10.1097/01.pat.0000461401.06779.80 ◽

2015 ◽

Vol 47 ◽

pp. S27

Author(s):

Cheng Yee Chan

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

Lateral Sclerosis

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Expanding the Spectrum of Movement Disorders Associated With C9orf72 Hexanucleotide Expansions

Neurology Genetics ◽

10.1212/nxg.0000000000000575 ◽

2021 ◽

Vol 7 (2) ◽

pp. e575

Author(s):

Carlos Estevez-Fraga ◽

Francesca Magrinelli ◽

Davina Hensman Moss ◽

Eoin Mulroy ◽

Giulia Di Lazzaro ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Movement Disorders ◽

Medical Records ◽

Multiple Comparisons ◽

Upper Limbs ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

Clinical Records ◽

Lateral Sclerosis

ObjectiveHexanucleotide repeat expansions (HREs) in C9orf72 are a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We aimed to determine the frequency and phenomenology of movement disorders (MD) in carriers of HRE in C9orf72 through a retrospective review of patients' medical records.MethodsWe retrospectively reviewed the clinical records of patients carrying a C9orf72 HRE in the pathogenic range and compared the characteristics of patients with and without MD.ResultsSeventeen of 40 patients with a C9orf72 HRE had a documented MD. In 6 of 17, MD were the presenting symptom, and in 2 of 17, MD were the sole manifestation of the disease. FTD was present in 13 of 17 patients, ALS in 5 of 17 patients, and 2 of 17 patients did not develop FTD or ALS. Thirteen of 17 patients had more than one MD. The most common MD were parkinsonism and tremor (resembling essential tremor syndrome), each one present in 11 of 17 patients. Distal, stimulus-sensitive upper limbs myoclonus was present in 6 of 17 patients and cervical dystonia in 5 of 17 patients. Chorea was present in 5 of 17 patients, 4 of whom showed marked orofacial dyskinesias. The most frequent MD combination was tremor and parkinsonism, observed in 8 of 17 patients, 5 of whom also had myoclonus. C9orf72 patients without MD had shorter follow-up times and higher proportion of ALS, although these results did not survive the correction for multiple comparisons.ConclusionsMD are frequent in C9orf72. They may precede signs of ALS or FTD, or even be present in isolation. Parkinsonism, tremor, and myoclonus are most commonly observed.

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