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

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.

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

“…Impairments in axonal trafficking have been closely linked with various neurodegenerative disorders, including ALS [ 65 ]. Motor neuron axons of patients with ALS have been observed to accumulate large quantities of phosphorylated neurofilament proteins and organelles, resulting in swelling along the length of the axons [ 66 , 67 ]. Though the exact mechanisms behind axonal transport dysregulation are unknown, research has found both anterograde and retrograde transport hindered in the presence of mutant SOD1 protein in isogenic mouse models prior to the development of ALS-like symptoms [ 68 , 69 ].…”

Association of Cerebrospinal Fluid Neurofilament Heavy Protein Levels With Clinical Progression in Patients With Parkinson Disease

“…This finding is in line with previous observations that NfH levels were associated with clinical progression in amyotrophic lateral sclerosis. 17 , 18 , 19 , 20 Cognitive impairment in PD is heterogeneous, and single or multiple cognitive domains can be affected in patients with PD who have cognitive impairment. 32 In the present study, cNfH levels were associated not only with decline in global cognition (MoCA), but also decline in domain-specific cognition, including visuospatial function (JLO), cognitive processing speed (SDM), verbal learning and memory (HVLT), executive function (SFT), and attention and working memory (LNS).…”

“… 16 Higher cNfH and blood NfH levels at baseline were associated with rapid progression of disease in patients with amyotrophic lateral sclerosis. 17 , 18 , 19 , 20 However, the association between the levels of NfH and clinical progression in patients with PD remains unclear.…”

The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis

“…Although pathogenic genes have been screened, the mechanism of MN degeneration is still not completely clear. At present, it is considered related to a long list of factors, among which are disturbances in RNA metabolism [16], protein misfolding and aggregation [17], marked neuromuscular junction (NMJ) abnormalities [18], immune system deficiency [19], nucleocytoplasmic transport defects [20], impaired DNA repair [21], excitotoxicity [22], mitochondrial dysfunction [23], oxidative stress [24], cytoskeletal derangements [25], axonal transport disruption [26], neuroinflammation [27], oligodendrocyte dysfunction [28] and vesicular transport defects [29].…”