A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease

Abstract

Amyotrophic lateral sclerosis (ALS) is an aggressive multifactorial disease converging on a common pathology: the degeneration of motor neurons (MNs), their axons and neuromuscular synapses. This vulnerability and dysfunction of MNs highlights the dependency of these large cells on their intracellular machinery. Neuronal microtubules (MTs) are intracellular structures that facilitate a myriad of vital neuronal functions, including activity dependent axonal transport. In ALS, it is becoming increasingly apparent that MTs are likely to be a critical component of this disease. Not only are disruptions in this intracellular machinery present in the vast majority of seemingly sporadic cases, recent research has revealed that mutation to a microtubule protein, the tubulin isoform TUBA4A, is sufficient to cause a familial, albeit rare, form of disease. In both sporadic and familial disease, studies have provided evidence that microtubule mediated deficits in axonal transport are the tipping point for MN survivability. Axonal transport deficits would lead to abnormal mitochondrial recycling, decreased vesicle and mRNA transport and limited signaling of key survival factors from the neurons peripheral synapses, causing the characteristic peripheral “die back”. This disruption to microtubule dependant transport in ALS has been shown to result from alterations in the phenomenon of microtubule dynamic instability: the rapid growth and shrinkage of microtubule polymers. This is accomplished primarily due to aberrant alterations to microtubule associated proteins (MAPs) that regulate microtubule stability. Indeed, the current literature would argue that microtubule stability, particularly alterations in their dynamics, may be the initial driving force behind many familial and sporadic insults in ALS. Pharmacological stabilization of the microtubule network offers an attractive therapeutic strategy in ALS; indeed it has shown promise in many neurological disorders, ALS included. However, the pathophysiological involvement of MTs and their functions is still poorly understood in ALS. Future investigations will hopefully uncover further therapeutic targets that may aid in combating this awful disease.

Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

“…These results suggest that the progressive degeneration of motor neurons in ALS patients with these mutations may result from changes in the MT cytoskeleton. Further, they add to an increasing body of evidence suggesting that various defects in MT dynamics and MT-dependent axonal transport lead to motor neuron degeneration in ALS [34], including those caused by mutations in dynein, kinesin, and tubulin itself [35–36]. In addition, some of the more common ALS-linked mutations such as in the RNA processing proteins TDP43 and FUS alter MT-dependent mRNA transport along motor neuron axons, and mutations in the ALS risk factor VEGF reduce the levels of MT-stabilizing microtubule-associated proteins [37].…”

Class I and II histone deacetylase expression is not altered in human amyotrophic lateral sclerosis: Neuropathological and positron emission tomography molecular neuroimaging evidence

“…In contrast to a previous study in which alterations in AcH3 and AcH4 in blood samples of PALS were assessed, we assessed these proteins in postmortem brain tissue. Furthermore, differences may be due to the variation in acetylated antibodies used in each study …”

“…It efficiently penetrates the blood–brain barrier and has high uptake in the cortex, cerebellum, and subcortical regions. It has shown good reproducibility and consistency in HDAC expression measurements in healthy human volunteers, with minimal off‐target binding in in vitro experiments to over 84 non‐HDAC central nervous system targets …”

“…The objectives of our study are (1) to evaluate class I and II HDAC protein and mRNA levels in a large sample of human postmortem brain and spinal cord tissue; (2) to assess acetylation of histones H3, H4, and α‐tubulin, downstream HDAC targets that were previously reported to be altered in ALS; and (3) to compare HDAC density in the brains of people living with ALS (PALS) versus HCs through the lens of [ 11 C]Martinostat, an HDAC Class I and IIb specific radioligand, by using positron emission tomography (PET).…”

“…The objectives of our study are (1) to evaluate class I and II HDAC protein and mRNA levels in a large sample of human postmortem brain and spinal cord tissue; (2) to assess acetylation of histones H3, H4, [20][21][22][23][24] and α-tubulin, 11,25 downstream HDAC targets that were previously reported to be altered in ALS [26][27][28]…”