Abstract
Spinobulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are two related motorneuron diseases (MNDs), both characterized by the presence of inclusions o aggregates of proteinaceous materials. In SBMA, aggregates contain mutant androgen receptors (AR) with an elongated polyglutamine tract (ARpolyQ), while in ALS aggregates contain TDP43, ubiquilin, optineurin, etc. Exceptions are familial ALS (fALS) forms linked to superoxide dismutase 1 (SOD1) mutations, in which aggregates are composed of mutant SOD1. Protein aggregation occurs when a large excess of proteins with aberrant conformations (misfolding) in produced and poorly cleared from the cells. Neurons contains an efficient protein quality control (PQC) system, but this may be insufficient to correctly remove misfolded proteins, especially during aging. The PQC system requires the activities of efficient chaperones and of the two major intracellular degradative systems: the ubiquitin-proteasome (UPS) and the autophagic systems. When misfolded protein are recognized by chaperones, they can be removed via autophagy by their engulfment into autophagosomes which then fuseto lysosomes. We found that motoneurons may responds to misfolded species by activating the expression of a small HSP, HSPB8, which facilitate the clearance of misfolded species via autophagy, usually acting by restoring the proper autophagic flux, found altered in MNDs. HSPB8 requires its co-chaperone BAG3. BAG3 binds the protein 14-3-3 and with this it interacts with dynein in a complex which also includes HSC70-CHIP. Dynein moves this large complex on the microtubules organization center where autophagosomes are assembled. Here, CHIP ubiquitinated misfolded protein substrates allowing their recognition by p62 and clearance from the motoneurons. Thus, together, the PQC and the HSPB8 proteins help to protect motoneurons from damages associated to the presence of aberrant protein species accumulating in affected cells.
Highlights
Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia
The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial, in contrast to one-trial, mild hypoxic preconditioning is apparently largely associated with the activation of CREB, as well as brain-derived neurotrophic factor (BDNF) and Bcl-2 overexpression
No significant differences in serum level of Solubile form of RAGE (sRAGE) where found between rapidly progressing and slow progressing subgroup of multiple sclerosis (MS) patients.Our results suggest for the role of sRAGE in MS ethiopathogenesis, but we did not find any association of sRAGE in serum with the rate of MS disability progression
Summary
Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia. The aim of the study was to characterize the effects of streptozocin (STZ)-indced diabetes on learning and memory of 5XFAD and wild-type (WT) mice in Morris water maze (MWM) at ages 2 and 6 months and on brain amyloid load. Existing evidence suggests GABAergic system is involved in pathophysiology of Alzheimer’s disease (AD) via inhibitory interneuron deficits (Verret et al, 2012) and decrease in functional GABAA receptors (Limon et al, 2012). Our concept: low doses of muscimol may prevent learning/memory deficits in intracerebroventricular (icv) streptozocin (STZ)-induced AD nontransgenic rat model. The Sigma-1 receptor is a chaperone protein that modulates intracellular calcium signalling of the endoplasmatic reticulum and is involved in learning and memory processes.The aim of the present study was to compare in vitro Ca2+ concentration modulating activity and in vivo behavioural effects of enantiomers of methylphenylpiracetam, a novel positive allosteric modulator of Sigma-1 receptors
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