Motoneuron disease are neurodegenerative disorder cause by degeneration of specific neurons localized in cerebral cortex or spinal cord. In particular, mutant proteins involved in familiar forms of Amyotrophic lateral sclerosis (ALS) and in Spinal and bulbar muscular atrophy (SBMA) 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 ubiquitin-proteasome (UPS) and autophagy system. We recently shown that facilitation of autophagy system by HSPB8 overexpression reduces misfolded proteins aggregation involved in ALS and SBMA, even when UPS is inhibited. Here, dynein seems to play a crucial role. In fact, dynein transports aggregate of misfolded proteins to microtubule organization center (MTOC), where proteins are assembled in aggresome that enter in the autophagy pathway. Dynein is also responsible for autophagosome formation, in fact it binds Ambra1-Beclin1-Vps34 complex that enable autophagosome nucleation. Immunofluorescence analysis on SBMA cell model showed that dynein co-localized with aggregates of mutant androgen receptor (AR) near MTOC and also in cytoplasm and neuropil. We thus perturbed dynein mediated transport with dynein ATPase activity inhibitor (EHNA) in cell model of ALS and SBMA. Unexpectedly EHNA drastically reduced aggregates of the mutant proteins SOD1G93A, TDP43ΔC and AR.Q46. Autophagic flux followed by western blot analysis of LC3II/LC3I ratio showed that EHNA blocked autophagy only when autophagy is induced by trehalose. These data correlate with previous observation that showing an increase of survival of the double mutant mice for SOD1 and dynein, indicating that dynein play a key role in the aggregating process in motoneurons.
Inhibition of ATPase activity of dynein reduce aggregates of misfolded proteins in motoneuron disease / R. Cristofani, E. Giorgetti, V. Crippa, A. Boncoraglio, P. Rusmini, A. Poletti. ((Intervento presentato al convegno Congresso ABCD tenutosi a Ravenna nel 20132.
|Titolo:||Inhibition of ATPase activity of dynein reduce aggregates of misfolded proteins in motoneuron disease|
CRISTOFANI, RICCARDO MARIA (Primo)
GIORGETTI, ELISA (Secondo)
POLETTI, ANGELO (Ultimo)
|Data di pubblicazione:||2013|
|Parole Chiave:||MND ; Autophagy ; EHNA ; misfolding|
|Settore Scientifico Disciplinare:||Settore BIO/13 - Biologia Applicata|
|Citazione:||Inhibition of ATPase activity of dynein reduce aggregates of misfolded proteins in motoneuron disease / R. Cristofani, E. Giorgetti, V. Crippa, A. Boncoraglio, P. Rusmini, A. Poletti. ((Intervento presentato al convegno Congresso ABCD tenutosi a Ravenna nel 20132.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|