C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside

Abstract

Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person's mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington's disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.

Keywords: Alzheimer's disease; STUB1; STUB1-associated disease.; amyotrophic lateral sclerosis; cerebellar ataxia; huntington disease; neurodegenerative diseases; parkinson's disease; polyglutamine diseases.

Fig. (1)

Post-translational modifications of CHIP. A) CDK5 mediated phosphorylation of mouse CHIP at serine 20 (S20) reduced CHIP- mediated ubiquitylation and proteasomal degradation of tAIF. B) AURKA phosphorylates CHIP at serine 273 (S273), promoting the ubiquitination and proteasomal degradation of AR. C) The ubiquitin-conjugating enzyme E2, UBE2W, promotes CHIP self-monoubiquitination, which enhances its ability to ubiquitinate and promote proteasomal degradation of polyQ expanded ataxin-3. AR: androgen receptor; AURKA: Aurora Kinase A; CDK5: cyclin-dependent kinase 5; CHIP: C-terminus of Hsp70 interacting protein; P: phosphorylation; polyQ: polyglutamine expansion; tAIF; truncated apoptosis inducing factor; Ub: ubiquitin; UBE2W: ubiquitin-conjugating enzyme E2 W.

Fig. (2)

CHIP regulation of PD-related proteins. 1) CHIP ubiquitinates α-synuclein oligomers for proteasomal degradation, thereby preventing their accumulation into fibrils and Lewy bodies. This process occurs in cooperation with the chaperones Hsp70 or Hsp90 and can be inhibited by BAG5. 2) CHIP positively regulates parkin-mediated ubiquitination of misfolded α-synuclein monomers, preventing their incorporation into oligomers. CHIP enhances parkin-mediated degradation of Pael-R by displacing Hsp70, which when bound to Pael-R, prevents its parkin-mediated ubiquitination. This prevents pathological accumulation of Pael-R into aggregates. 3) With Hsp90, CHIP has been shown to facilitate proteasomal degradation of LRRK2. 4) With Hsp70, CHIP has been shown to facilitate proteasomal degradation of PINK1. 5) In response to oxidative stress and genetic polymorphisms, abnormal mitochondria are targeted for degradation in a PINK1- and Parkin-dependent manner via mitophagy. CHIP inhibits nuclear translocation of the mitochondrial protein EndoG, a process that is accelerated in the presence of misfolded α-synuclein and results in dopaminergic cell death. 6) CHIP promotes degradation of Lewy bodies by autophagy. α-syn: α-synuclein; BAG5: BCL2 associated athanogene 5; CHIP; C-terminus of Hsp70 interacting protein; EndoG: endonuclease G; Hsp70: Heat shock protein 70; Hsp90: Heat shock protein 90; LRRK2: Leucine rich repeat kinase 2; PINK1: PTEN-induced protein kinase; Pael-R: Parkin-associated endothelin receptor-like receptor; Ub: Ubiquitin.

Fig. (3)

CHIP regulation of AD-related proteins. 1) CHIP together with Hsp70 or Hsp90 can recognize hyperphosphorylated tau, promote its ubiquitination and target it for proteasomal degradation. Akt enhances MARK2 activity, which prevents hyperphosphorylated tau recognition by CHIP. 2) HDAC6 inhibits HSP90-mediated refolding of tau, promoting aggregate formation. CHIP can promote the proteasomal degradation of HDAC6, enhancing HSP90 activity and reducing tau accumulation. 3) CHIP interacts with and ubiquitinates APP, targeting it for proteasomal degradation and is also able to decrease amyloid beta accumulation. 4) BACE1 promotes cleavage of APP into the pathogenic Aβ42 form, which promotes amyloid β plaque formation. CHIP is able to reduce BACE1 levels through ubiquitination of BACE1, through its stabilization of the transcription factor p53 which negatively regulates BACE1 transcription. AAP: amyloid precursor protein; Aβ42; 42 amino acid form of amyloid beta; Akt: Protein kinase B; BACE-1: beta-secretase-1; CHIP: C-terminus of Hsp70 interacting protein; Hsp70: Heat shock protein 70; Hsp90: Heat shock protein 90; HDAC6: Histone deacetylase 6; MARK2: Microtubule affinity regulating kinase 2; p53: tumor protein 53; Ub: Ubiquitin.

Fig. (4)

CHIP regulation of ALS-related proteins. CHIP together with Hsp70 can target mutant SOD1 for proteasomal degradation. Aggregation of mutant SOD1 may impair proteasomal function. CHIP together with Hsp70, BAG3 and HSPB8 can mediate SOD1 mutant aggregate degradation independent of the proteasome, by facilitating autophagosome formation, leading to autophagy-lysosome mediated degradation of mutant SOD1 aggregates. BAG3; BCL2-associated athanogene 3; CHIP: C-terminus of Hsp70-interacting protein; Hsp70: Heat shock protein 70; SOD1: Superoxide dismutase; HSPB8; Heat shock protein Beta-8; p62: nucleoporin p62; Ub: ubiquitin.

Fig. (5)

CHIP regulation of proteins involved in LD. Loss of function of malin or laforin results in hyperphosphorylated insoluble glycogen which promotes the formation of polyglucosan aggregates termed Lafora bodies. CHIP increases wildtype malin proteins in a concentration dependent manner through an unknown mechanism. CHIP: C-terminus of Hsp70 interacting protein.

Fig. (6)

CHIP regulation of polyQ expanded proteins. A) Within HD disease models, CHIP reduces polyQ-HTT aggregation. High levels of HSPBP1 inhibits CHIP-mediated reductions in polyQ-HTT aggregation. B) Within a model of SBMA, CHIP overexpression promotes proteasomal degradation of polyQ-AR and reduced polyQ-AR nuclear accumulation. C) Within a SCA3 model of disease, self-monoubiquitination of CHIP with UBE2W promotes ubiquitination and proteasomal degradation of polyQ-ataxin-3. PolyQ-ataxin-3, a DUB, promotes deubiquitination of CHIP, reducing polyQ-ataxin-3 ubiquitination and degradation. D) Within a SCA1 model of disease, CHIP is able to reduce polyQ-ataxin-1 aggregation. AR: androgen receptor; CHIP: C-terminus of Hsp70 interacting protein; polyQ: polyglutamine expansion; HSPBP1: Hsp70 binding protein 1; HTT; huntingtin protein; SBMA; spinal and bulbar muscular atrophy; Ub: ubiquitin; UBE2W; ubiquitin- conjugating enzyme E2 W.

Fig. (7)

Mutations identified among individuals with STUB1-associated disease. CHIP is a 303 amino acid protein that contains an N-terminal tetratricopeptide (TPR) domain (which interacts with Hsp70 and Hsp90), a coiled-coil domain (which mediates asymmetric homodimerization of CHIP), and a C-terminal U-box domain (which confers E3 ubiquitin ligase activity). Sixty-nine different STUB1 mutations have been reported to be associated with ataxia, 62 of which are present within exons. The locations of each mutation in the protein are shown in the schematic figure with an arrow. Arrows of the same colour indicate compound heterozygous mutations which have been identified together. The most frequent observed mutation is L275Dfs*16 (Mutation #64). Additional details regarding each mutation are listed in Table (1), including results from computational in silico prediction programs. Where the number of patients with this mutation is listed as NA, mutations were reported in a WES study which did not report patient numbers. cDNA: coding DNA; NA: not available.