Proposed association between the hexanucleotide repeat of C9orf72 and opposability index of the thumb

Zhongbo Chen,Kuang Lin,Jeffrey D Macklis,Ammar Al-Chalabi

doi:10.1080/21678421.2016.1257024

Abstract

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron and sub-cerebral projection neuron degeneration. We sought to explore the particular susceptibility of humans to neurodegeneration and whether any characteristic human features might predispose to selective vulnerability of the critical motor circuitry in ALS. The pathophysiology of the C9orf72 repeat is not yet understood, despite its role as a common cause of ALS and frontotemporal dementia. Methods: We examined the development of the monosynaptic cortico-motoneuronal system, key to skilled hand movements, measured by the thumb opposability index, and its relationship to the C9orf72 hexanucleotide repeat expansion, a strong predisposing factor for neurodegeneration, using the genomic tool BLAST. Results: We found a statistically significant linear relationship between the C9orf72 hexanucleotide bit score, a measure of genomic conservation of the aligned region across different species, and the thumb opposability index (Pearson’s correlation coefficient of 0.78, p value 0.023). The C9orf72 hexanucleotide repeat was only found in humans, chimpanzees and gorillas, species with higher opposability indices. Conclusions: This may support a role of the hexanucleotide repeat in the same developmental pathways in species with higher prehensility, which may be associated with the selective vulnerability of cortico-motoneuronal cells in humans, manifested most obviously as the ‘split hand’ syndrome in ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease manifesting as a syndrome of unremitting progressive motor weakness, cognitive impairment, and ultimate respiratory failure
We examined the development of the monosynaptic cortico-motoneuronal system, key to skilled hand movements, measured by the thumb opposability index, and its relationship to the C9orf72 hexanucleotide repeat expansion, a strong predisposing factor for neurodegeneration, using the genomic tool Basic Local Alignment Search Tool (BLAST)
The correlation suggests that the C9orf72 hexanucleotide region may have a role in the same developmental pathways that are important in animals with higher opposability indices, for example in the development of the corticospinal motor neuron-to-spinal motor neuron circuitry, for voluntary motor dexterity

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease manifesting as a syndrome of unremitting progressive motor weakness, cognitive impairment, and ultimate respiratory failure. The central pathology involves the degeneration of both corticospinal and spinal motor neurons. We sought to explore the particular vulnerability of humans to neurodegeneration in these central neuronal populations, and whether the evolutionary development of any characteristic human features might predispose to the selective vulnerability in ALS. The development of a monosynaptic cortico-motoneuronal system is a key contributor to the capacity for skilled finger movements [9,10]. This system may render an increased susceptibility to motor neuron degeneration [6], and an increase in human survival may unmask selective connectome-based vulnerability

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Discussion

Conclusion