Protein aggregation and degradation mechanisms in neurodegenerative diseases

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 mutations 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.

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

Figure 1

The main parallel strategies to maintain protein homeostasis. The misfolded proteins may be refolded, degraded, or sequestered within cells. All these mechanisms centrally involve the function of different molecular chaperones, such as heat shock proteins (Hsps). Abbreviations: ALIS, aggresome-like inducible structure; ALP, autophagosome-lysosome system; IPOD, insoluble protein deposit; JUNQ, juxtanuclear quality control; UPS, ubiquitin-proteasome system.

Figure 2

Protein sequestration into different compartments. The misfolded or aggregated proteins may be targeted to different intracellular compartments. After misfolding, most proteins are recognized and ubiquitinated, which directs them to the JUNQ, a region that contains chaperones and 26S proteasomes. JUNQ concentrates soluble misfolded proteins, which may be proteasomally degraded or refolded by the chaperones. The insoluble aggregated proteins which may not be ubiquitinated, such as HD-associated huntingtin or prions, can be targeted to IPOD. It does not contain proteasomes, but colocalizes with autophagy-associated proteins, such as Atg8. Aggregated proteins can also be targeted to the aggresomes, which localize at the MTOC, are surrounded by a vimentin envelope, and cause an indentation of the nucleus. Aggresomes also contain chaperones and components of the ubiquitin-proteasome system (UPS). Targeting to the aggresomes, IPOD, or JUNQ involves active retrograde transport of the cargo by the motor proteins on the microtubules. Immune activation or stress conditions may induce the formation of transient ALIS inclusions. These colocalize with ubiquitin and p62/SQSTM1 and concentrate soluble proteins targeted to clearance by the UPS or autophagy. Abbreviations: ALIS, aggresome-like induced structure; IPOD, insoluble protein deposit; JUNQ, juxtanuclear quality control; MT, microtubule; MTOC, microtubule-organizing center; N, nucleus.

Figure 3

Ubiquilin-1 transcript variants (TV). The full-length ubiquilin-1 TV1 is encoded by 11 exons. Ubiquilin-1 has two signature domains of ubiquitin-like proteins: The N-terminal UBL (ubiquitin-like) domain (orange) and the C-terminal UBA (ubiquitin-associated) domain (green). UBA binds to polyubiquitinated proteins and UBL mediates interaction with the proteasome. The central region consists of conserved asparagine- and proline-rich repeats that mediate ubiquilin-1 interaction with other proteins. TV2 lacks exon 8 (light blue). TV3 lacks exons 2, 3, and 4 and therefore has an incomplete UBL domain. TV4 contains the first 3 exons and a unique short C-terminus (grey) due to a frame shift leading to a 32-amino acid insertion after the exon 3/5 junction.