Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content

Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset neurological disorder characterized by death of motoneurons. Mutations in Cu/Zn superoxide dismutase-1 (SOD1) cause familial ALS but the mechanisms whereby they induce disease are not fully understood. Here, we use time-lapse microscopy to monitor for the first time the effect of mutant SOD1 on fast axonal transport (FAT) of bona fide cargoes in living neurons. We analyzed FAT of mitochondria that are a known target for damage by mutant SOD1 and also of membrane-bound organelles (MBOs) using EGFP-tagged amyloid precursor protein as a marker. We studied FAT in motor neurons derived from SOD1G93A transgenic mice that are a model of ALS and also in cortical neurons transfected with SOD1G93A and three further ALS-associated SOD1 mutants. We find that mutant SOD1 damages transport of both mitochondria and MBOs, and that the precise details of this damage are cargo-specific. Thus, mutant SOD1 reduces transport of MBOs in both anterograde and retrograde directions, whereas mitochondrial transport is selectively reduced in the anterograde direction. Analyses of the characteristics of mitochondrial FAT revealed that reduced anterograde movement involved defects in anterograde motor function. The selective inhibition of anterograde mitochondrial FAT enhanced their net retrograde movement to deplete mitochondria in axons. Mitochondria in mutant SOD1 expressing cells also displayed features of damage. Together, such changes to mitochondrial function and distribution are likely to compromise axonal function. These alterations represent some of the earliest pathological features so far reported in neurons of mutant SOD1 transgenic mice.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Altered microtubule-dependent trafficking associated with the damaged transport of mitochondria was identified in ALS [127]. Microtubule trafficking is affected by the acetylation of α-tubulin through the HAT ELP3 [128], and allelic variants of ELP3 were associated with sporadic cases of ALS [129].…”

Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis

“…It should be noted that the oscillations of this system do not necessarily represent the relapsing and remitting of functional deficits, such as is seen with multiple sclerosis, but rather the oscillations of individual mechanisms and pathways. In fact, such oscillations could be responsible for small fluctuations sometimes seen within and among mechanistic studies, such as those examining axonal transport (De Vos, Chapman et al 2007) and protein aggregation (Stieber, Gonatas et al 2000;Gould, Buss et al 2006). How oscillations correlating with specific losses in muscle function remains to be seen.…”

Role of Mitochondrial Dysfunction in Motor Neuron Degeneration in ALS

“…Changes in the speed of anterograde and retrograde transport (Breuer & Atkinson, 1988;Breuer et al, 1987;Sasaki & Iwata, 1996), as well as neurofilament disorganization and accumulation of mitochondria, vesicles and smooth endoplasmic reticulum have been described in peripheral nerves of ALS patients (Hirano et al, 1984a, b;Sasaki & Iwata, 1996). These alterations in axonal transport have been observed also in transgenic models of FALS, which have allowed the study of their progression and the molecular machinery involved (Bilsland et al, 2010;Brunet et al, 2009;Collard et al, 1995;De Vos et al, 2007;Ligon et al, 2005;Perlson et al, 2009;Pun et al, 2006;Tateno et al, 2009;Warita et al, 1999;Williamson & Cleveland, 1999). In mutant SOD1 (mSOD1) rodents, some motor proteins such as: dynein, dynactin, kinesin, myosin, actin, and microtubules and neurofilaments are affected by mSOD1 aggregates (Breuer & Atkinson, 1988;Breuer et al, 1987;Collard et al, 1995;Ligon et al, 2005;Sasaki & Iwata, 1996;Williamson & Cleveland, 1999;Zhang et al, 2007).…”