Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: Implication for protein aggregation and immune response
Articolo
Data di Pubblicazione:
2012
Citazione:
Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: Implication for protein aggregation and immune response / C. Bendotti, M. Marino, C. Cheroni, E. Fontana, V. Crippa, A. Poletti, S. De Biasi. - In: PROGRESS IN NEUROBIOLOGY. - ISSN 0301-0082. - 97:2(2012 May), pp. 101-126.
Abstract:
The ubiquitin-proteasome system (UPS) is the major intracellular proteolytic mechanism controlling the
degradation of misfolded/abnormal proteins. A common hallmark in amyotrophic lateral sclerosis (ALS)
and in other neurodegenerative disorders is the accumulation of misfolded/abnormal proteins into the
damaged neurons, leading to the formation of cellular inclusions that are mostly ubiquitin-positive.
Although proteolysis is a complex mechanism requiring the participation of different pathways, the
abundant accumulation of ubiquitinated proteins strongly suggests an important contribution of UPS to
these neuropathological features. The use of cellular and animal models of ALS, particularly those
expressing mutant SOD1, the gene mutation most represented in familiar ALS, has provided significant
evidence for a role of UPS in protein inclusions formation and motor neuron death. This review will
specifically discuss this piece of evidence and provide suggestions of potential strategies for therapeutic
intervention. We will also discuss the finding that, unlike the constitutive proteasome subunits, the
inducible subunits are overexpressed early during disease progression in SOD1 mice models of ALS. These
subunits form the immunoproteasome and generate peptides for the major histocompatibility complex
class I molecules, suggesting a role of this system in the immune responses associated with the pathological
features of ALS. Since recent discoveries indicate that innate and adaptive immunity may influence the
disease process, in this review we will also provide evidence of a possible connection between immuneinflammatory
reactions and UPS function, in the attempt to better understand the etiopathology of ALS and
to identify appropriate targets for novel treatment strategies of this devastating disease.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Motorneuron diseases ; Amyotrophic Lateral Sclerosis ; Proteasome ; HSPB8
Elenco autori:
C. Bendotti, M. Marino, C. Cheroni, E. Fontana, V. Crippa, A. Poletti, S. De Biasi
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