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Am J Neurodegener Dis 2013;2(1):1-14

Original Article
Protein aggregation and degradation mechanisms in neurodegenera-tive
diseases

Mari Takalo, Antero Salminen, Hilkka Soininen, Mikko Hiltunen, Annakaisa Haapasalo

Institute of Clinical Medicine – Neurology, University of Eastern Finland and Department of Neurology, Kuopio
University Hospital, Kuopio, Finland

Received November 29, 2012; Accepted January 18, 2013; Epub March 8, 2013; Published March 18, 2013

Abstract: Neurodegenerative diseases are characterized by selective neuronal vulnerability and neurodegeneration in
specific brain regions. The pathogenesis of these disorders centrally involves abnormal accumulation and
aggregation of specific proteins, which are deposited in intracellular inclusions or extracellular aggregates that are
characteristic for each disease. Increasing evidence suggests that genetic muta-tions or environmental factors can
instigate protein misfolding and aggregation in these diseases. Consequently, neurodegenerative diseases are often
considered as conformational diseases. This idea is further supported by studies implicating that impairment of the
protein quality control (PQC) and clearance systems, such as the ubiquitin-proteasome system and autophagosome-
lysosome pathway, may lead to the abnormal accumulation of disease-specific proteins. This suggests that similar
pathological mechanisms may underlie the pathogenesis of the different neurodegenerative disorders. Interestingly,
several proteins that are known to associate with neurodegenerative diseases have been identified as important
regulators of PQC and clearance systems. In this review, we summarize the central features of abnormal protein
accumulation in different common neurodegenerative diseases and discuss some aspects of specific disease-
associated proteins regulating the PQC and clearance mechanisms, such as ubiquilin-1. (AJND1211003)

Keywords: Protein quality control, ubiquitin-proteasome system, autophagy, protein misfolding, neurodegenerative
diseases, inclusion body, aggresome, IPOD, JUNQ, ubiquilin-1

Address correspondence to: Dr. Annakaisa Haapasalo, Institute of Clinical Medicine – Neurology, University of
Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Tel: +358 40 3552768; Fax: +358 17 162048; E-mail:
annakaisa.haapasalo@uef.fi