Pharmacological inhibition of dynein movement reduces aggregation of misfolded proteins in motoneuron diseases

Amyotrophic lateral sclerosis (ALS) and Spinal and bulbar muscular atrophy (SBMA) are two familiar forms with adult onset of motoneuron disease (MNDs). Mutant proteins involved in these disease, Androgen receptor (AR), SOD1 and TDP43 respectively, tend to acquire aberrant conformations (misfolding) that lead to their aggregation. Aggregates may be protective by subtracting misfolded proteins, but may also cause impairment of proteasome and autophagy. These are the bigger actor involved in protein quality control system (PQC). We recently shown that facilitation of autophagy by HSPB8 overexpression reduces misfolded proteins aggregation, even when proteasome is inhibited. Here, dynein seems to play a crucial role. In fact, dynein transports misfolded proteins to microtubule organization center (MTOC), where proteins are assembled in aggresome to be degraded by autophagy. Dynein also mediates autophagosome formation, by binding Ambra1-Beclin1-Vps34 complex that enable autophagosome nucleation. In a SBMA cell model we found that dynein co-localized with aggregates of mutant androgen receptor (AR) near MTOC. When we perturbed dynein mediated transport with dynein ATPase activity inhibitor (EHNA) in cell model of SBMA and ALS we found a drastic reduction of aggregates of the mutant proteins ARpolyQ, mutSOD1, and mutTDP43. EHNA, also, increased solubility of misfolded ARpolyQ. Our data are in line with previous observation that showing an increase of survival of the double mutant mice for mutSOD1 and an inactive form of dynein. This suggests that dynein may mediates aggregates formation process during the PQC response