Abstract
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.
Highlights
Neurons have unique and specialized morphological features that enable them to receive, process and transmit information [1]
Genomic variants that contribute to cytoskeletal dysregulation in amyotrophic lateral sclerosis (ALS) In ALS and other neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and CMT, a common pathological hallmark is the formation of neuronal cytoplasmic inclusions containing intermediate filament proteins such as Neurofilament light (NEFL), Neurofilament medium (NEFM), Neurofilament heavy (NEFH) and PRPH [36–38]
An individual with slowly progressive, chronic axonal distal motor neuropathy and the extrapyramidal syndrome has been reported to carry variants in DCTN1, KIF5A and NEFH genes [81]. These findings demonstrate that mutations/variation in key genes involved in cytoskeletal organization and axonal transport can have a detrimental impact on structural organization, resulting in disrupted mitochondrial transport in neurons
Summary
Neurons have unique and specialized morphological features that enable them to receive, process and transmit information [1]. Dynamics and stability of cytoskeletal proteins, as a result of mutations or alterations in Theunissen et al Translational Neurodegeneration (2021) 10:46 molecular pathways involved in axonal transport, are associated with the formation of protein aggregates in neurons and glia of the central nervous system (CNS) [3, 6].
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