By Jessica Lu
Polyglutamine diseases are a group of nine inherited neurodegenerative diseases: Huntington’s disease (HD), Dentato-rubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7 and 17. The onset of these diseases typically occurs in midlife and they slow to progress.1 Although the genes that are mutated in each of these nine diseases are unrelated, they are all caused by the expansion of CAG repeats (above 35-40 repeats) within the mutated genes.2,3 As CAG encodes glutamine, the affected disease proteins contain extended polyglutamine tracts and, generally, the age of disease onset is inversely correlated with polyglutamine tract length.1 Patients suffer from progressive neuronal cell loss within regions of the brain or spinal cord with the specific region from which neurons are lost depending on the disease, resulting in neurological impairments specific to each disease.3 It is crucial to understand why the expansion of CAG repeats causes disease to develop effective therapies for polyglutamine diseases and whilst many mechanisms underlying polyglutamine diseases have been proposed, the true mechanism remains a mystery.4
One possibility is that the extended polyglutamine tracts in disease proteins drive disease because of their ability to induce protein aggregation.1 Protein aggregation is associated with many neurodegenerative diseases. For example, Alzheimer’s disease is associated with aggregation of the β-amyloid peptide and the tau protein.5 A variety of in vitro studies have shown that the extended polyglutamine tract in affected proteins undergoes a conformational change from a random coil to a β-sheet-rich monomer. The β-sheet-rich monomer can aggregate to form soluble oligomers, which then further aggregate to form amyloid fibrillar structures. In addition, protein domains that are rich in glutamine have high propensity to form α-helical coiled-coil secondary structures. These α-helical coiled-coils can also assemble into oligomers and increase aggregation and toxicity in cultured cells.3
Additionally, many studies have proposed that disruptive interactions between disease proteins and cellular components driving polyglutamine disease pathology. The α-helical coiled-coil conformation of disease proteins has been found to be prominently involved in protein-protein interaction.3 These protein-protein interactions disrupt many downstream pathways, including pathways critical for cellular homeostasis as well as pathways involved in gene regulation at transcriptional or post-transcriptional steps. The disruptive interactions include both gain of function and loss of function mechanisms.6 For example, some proximate mechanisms implicated in Huntington’s disease include impaired nucleocytoplasmic transport, DNA damage and repair, mitochondrial dysfunction, altered neuronal cholesterol metabolism and altered axonal transport. Studies of other polyglutamine diseases share similar findings in that many important pathways are disrupted.6
Interestingly, there is evidence that when the expanded CAG repeats are interrupted with the CAA codon (a synonymous codon that also codes for glutamine), the resulting diseases are pathologically different than those caused by only CAG repeat expansion. The resulting protein sequence in both cases would be indistinguishable, suggesting that the mechanism of disease cannot solely be explained by the expanded disease proteins.4 One possible idea is that the expanded CAG codon repeats cause translation stress due to depletion of the charged glutaminyl-transfer RNA (tRNA) that pairs exclusively to the CAG codon, tRNAGln-CUG. The depletion of tRNAGln-CUG might possibly result in ribosomal frameshifting, thus producing various mistranslated protein species.4 This is evidenced by the presence of mistranslated protein species in alternative reading frames in post-mortem brains of individuals with Huntington’s disease and spinocerebellar ataxia type 3.4 Moreover, the various mistranslated species generated from frameshifting may be more likely to undergo the conformational changes that lead to protein aggregation, providing yet another possible explanation for the mechanism of disease.4,7
Following on from the idea that tRNAGln-CUG depletion causes ribosomal frameshifting, it is possible that not only is the translation of disease proteins affected by frameshifting, but also the translation of other endogenous cellular proteins.4 Transcripts of genes containing a high number of CAG codons could be at increased risk of frameshifting when the levels of tRNAGln-CUG are in a depleted state. Supporting this hypothesis is the fact that other genes implicated in Huntington’s disease also commonly contain CAG tracts, such as the genes encoding CREB-binding protein (CBP) (a transcription activator and histone acetyltransferase) and forkhead box protein P2 (a transcription factor).4 Because these genes are involved in transcription regulation, this provides an explanation for the transcription misregulation observed in Huntington’s disease. Furthermore, mistranslation of other endogenous cellular proteins may explain why polyglutamine diseases share similar pathologies, even though the genes mutated for each disease are unrelated.4
In summary, polyglutamine diseases may be caused by aggregation of diseased proteins, disruption of critical cellular pathways, or translation stress due to the expansion of CAG repeats. Better understanding of the underlying causes of polyglutamine diseases will, thus, hopefully improve the development of effective therapies in future.
(1) Nagehan Ersoy Tunalı ED1 – Nagehan Ersoy Tunalı. Molecular Mechanisms of Polyglutamine Pathology and Lessons Learned from Huntington’s Disease. Neurodegenerative Diseases. Rijeka: IntechOpen; 2021. pp. Ch. 7. Available from: doi: 10.5772/intechopen.93508
(2) Khare SD, Ding F, Gwanmesia KN, Dokholyan NV. Molecular Origin of Polyglutamine Aggregation in Neurodegenerative Diseases. PLOS Computational Biology. 2005; 1 (3): e30. Available from: doi.org/10.1371/journal.pcbi.0010030 .
(3) Minakawa EN, Nagai Y. Protein Aggregation Inhibitors as Disease-Modifying Therapies for Polyglutamine Diseases. Frontiers in Neuroscience. 2021; 0 Available from: doi: 10.3389/fnins.2021.621996
(4) Buhr F, Ciryam PS, Vendruscolo M. A mistranslation-prone transcriptome underlying polyglutamine expansion diseases. Nature Reviews Molecular Cell Biology. 2021; 22 (9): 583-584. Available from: doi: 10.1038/s41580-021-00368-4
(5) Murphy MP, LeVine H,3rd. Alzheimer’s disease and the amyloid-beta peptide. Journal of Alzheimer’s disease : JAD. 2010; 19 (1): 311-323. Available from: doi: 10.3233/JAD-2010-1221 [doi] .
(6) Lieberman AP, Shakkottai VG, Albin RL. Polyglutamine Repeats in Neurodegenerative Diseases. Annual Review of Pathology: Mechanisms of Disease. 2019; 14 (1): 1-27. Available from: doi: 10.1146/annurev-pathmechdis-012418-012857
(7) Girstmair H, Saffert P, Rode S, Czech A, Holland G, Bannert N, et al. Depletion of Cognate Charged Transfer RNA Causes Translational Frameshifting within the Expanded CAG Stretch in Huntingtin. Cell Reports. 2013; 3 (1): 148-159. Available from: doi: 10.1016/j.celrep.2012.12.019