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Key Words: CAG repeats, GGC repeats, androgen receptor, clinical significance of polyglutamine repeats, polyglutamine tract

Mitochondrial dysfunction is implicated in multiple neurodegenerative diseases. In order to maintain a healthy population of functional mitochondria in cells, defective mitochondria must be properly eliminated by lysosomal machinery in a process referred to as mitophagy. Here, we uncover a new molecular mechanism underlying mitophagy driven by glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) under the pathological condition of Huntington's disease (HD) caused by expansion of polyglutamine repeats. Expression of expanded polyglutamine tracts catalytically inactivates GAPDH (iGAPDH), which triggers its selective association with damaged mitochondria in several cell culture models of HD. Through this mechanism, iGAPDH serves as a signaling molecule to induce direct engulfment of damaged mitochondria into lysosomes (micro‐mitophagy). However, abnormal interaction of mitochondrial GAPDH with long polyglutamine tracts stalled GAPDH‐mediated mitophagy, leading to accumulation of damaged mitochondria, and increased cell death. We further demonstrated that overexpression of inactive GAPDH rescues this blunted process and enhances mitochondrial function and cell survival, indicating a role for GAPDH‐driven mitophagy in the pathology of HD. Synopsis GAPDH is a mediator of cytoprotective micro‐mitophagy, the process by which damaged mitochondria are directly engulfed by lysosomes for degradation. Mutant huntingtin with expanded polyglutamine repeats, however, disrupts this process, contributing to the pathology of Huntington's disease. GAPDH selectively associates with damaged mitochondria in cells expressing mutant huntingtin. Mutant huntingtin interacts with mitochondrial GAPDH. The interaction inhibits GAPDH‐driven micro‐mitophagy, leading to accumulation of damaged mitochondria in cells. Overexpression of GAPDH rescues this blunted mitophagy, enhancing mitochondrial functions and promoting cell survival. Graphical Abstract GAPDH is a mediator of cytoprotective micro‐mitophagy, the process by which damaged mitochondria are directly engulfed by lysosomes for degradation. Mutant huntingtin with expanded polyglutamine repeats, however, disrupts this process, contributing to the pathology of Huntington's disease.

Huntington’s disease (HD) is a fatal and pure genetic disease with a progressive loss of medium spiny neurons (MSN). HD is caused by expanded polyglutamine repeats in the exon 1 of HD gene. Clinically, HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. Several years of intense research revealed that multiple cellular changes, including defective axonal transport, protein-protein interactions, defective bioenergetics, calcium dyshomeostasis, NMDAR activation, synaptic damage, mitochondrial abnormalities, and selective loss of medium spiny neurons are implicated in HD. Recent research on mutant huntingtin (mHtt) and mitochondria has found that mHtt interacts with the mitochondrial division protein, dynamin-related protein 1 (DRP1), enhances GTPase DRP1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. Recent research also revealed that failure to remove dead and/or dying mitochondria is an early event in the disease progression. Currently, efforts are being made to reduce abnormal protein interactions and enhance synaptic mitophagy as therapeutic strategies for HD. The purpose of this article is to discuss recent research in HD progression. This article also discusses recent developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.

Emerging evidence suggests that DNA repair deficiency and genome instability may be the impending signs of many neurological diseases. Genome-wide association (GWAS) studies have established a strong correlation between genes that play a role in DNA damage repair and many neurodegenerative diseases, including Huntington’s disease (HD), and several other trinucleotides repeat expansion-related hereditary ataxias. Recently, many reports have documented a significant role played by the DNA repair processes in aging and in modifying many neurodegenerative diseases, early during their progression. Studies from our lab and others have now begun to understand the mechanisms that cause defective DNA repair in HD and surprisingly, many proteins that have a strong link to known neurodegenerative diseases seem to be important players in these cellular pathways. Mutations in Huntingtin (HTT) gene that lead to polyglutamine repeat expansion at the N-terminal of HTT protein has been shown to disrupt transcription-coupled DNA repair process, a specialized DNA repair process associated with transcription. Due to the recent progress made in understanding the mechanisms of DNA repair in relation to HD, in this review, we will mainly focus on the mechanisms by which the wildtype huntingtin (HTT) protein helps in DNA repair during transcription, and the how polyglutamine expansions in HTT impedes this process in HD. Further studies that identify new players in DNA repair will help in our understanding of this process in neurons. Furthermore, it should help us understand how various DNA repair mechanism(s) coordinate to maintain the normal physiology of neurons, and provide insights for the development of novel drugs at prodromal stages of these neurodegenerative diseases.

Background Huntington disease (HD) is a neurodegenerative disease where a genetic mutation leads to excessive polyglutamine (Q) repeats in the huntingtin protein. The polyglutamine repeats create toxic plaques when the protein is cleaved, leading to neuron death. The glycolipid GM1 ganglioside (GM1) has been shown to be neuroprotective in HD models, as it prevents the cleavage of the mutant huntingtin protein by phosphorylation of serine 13 and 16. Previous studies have tested GM1 in both adult-onset and juvenile-onset HD models, but this study set out to investigate whether GM1 mediated cytoprotection is influenced by the length of polyglutamine repeats. Method and result This study utilized cell culture to analyze the effect of GM1 on cell viability, directly comparing the response between cells with adult-onset HD and juvenile-onset HD. HEK293 cells expressing either wild-type huntingtin (Htt) (19Q) exon 1, adult-onset HD mutant Htt exon 1 (55Q), or Juvenile HD mutant Htt exon 1 (94Q) were assessed for cell viability using the WST-1 assay. Our results suggested moderate doses of GM1 increased cell viability for all cell lines when compared to untreated cells. When comparing HEK293 55Q and 94Q cells, there was no difference in cell viability within each dose of GM1. Conclusion These data suggest cellular responses to GM1 are independent of polyglutamine repeats in HD cells and provide insight on GM1’s application as a therapeutic agent for HD and other diseases.

Extrapyramidal movement disorders include hypokinetic rigid and hyperkinetic or mixed forms, most of them originating from dysfunction of the basal ganglia (BG) and their information circuits. The functional anatomy of the BG, the cortico-BG–thalamocortical, and BG–cerebellar circuit connections are briefly reviewed. Pathophysiologic classification of extrapyramidal movement disorder mechanisms distinguish (1) parkinsonian syndromes, (2) chorea and related syndromes, (3) dystonias, (4) myoclonic syndromes, (5) ballism, (6) tics, and (7) tremor syndromes. Recent genetic and molecular–biologic classifications distinguish (1) synucleinopathies (Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease–dementia, and multiple system atrophy); (2) tauopathies (progressive supranuclear palsy, corticobasal degeneration, FTLD-17; Guamian Parkinson–dementia; Pick’s disease, and others); (3) polyglutamine disorders (Huntington’s disease and related disorders); (4) pantothenate kinase-associated neurodegeneration; (5) Wilson’s disease; and (6) other hereditary neurodegenerations without hitherto detected genetic or specific markers. The diversity of phenotypes is related to the deposition of pathologic proteins in distinct cell populations, causing neurodegeneration due to genetic and environmental factors, but there is frequent overlap between various disorders. Their etiopathogenesis is still poorly understood, but is suggested to result from an interaction between genetic and environmental factors. Multiple etiologies and noxious factors (protein mishandling, mitochondrial dysfunction, oxidative stress, excitotoxicity, energy failure, and chronic neuroinflammation) are more likely than a single factor. Current clinical consensus criteria have increased the diagnostic accuracy of most neurodegenerative movement disorders, but for their definite diagnosis, histopathological confirmation is required. We present a timely overview of the neuropathology and pathogenesis of the major extrapyramidal movement disorders in two parts, the first one dedicated to hypokinetic-rigid forms and the second to hyperkinetic disorders.

Extrapyramidal movement disorders comprise hypokinetic-rigid and hyperkinetic or mixed forms, most of them originating from dysfunction of the basal ganglia (BG) and their information circuits that have been briefly reviewed in part 1 of the papers on neuropathology and pathogenesis of extrapyramidal movement disorders. The classification of hyperkinetic forms distinguishes the following: (1) chorea and related syndromes; (2) dystonias (dyskinesias); (3) tics and tourette disorders; (4) ballism; (5) myoclonic and startle disorders; and (6) tremor syndromes. Recent genetic and molecular classification distinguishes the following: (1) polyglutamine disorders (Huntington’s disease and related disorders); (2) pantothenate kinase associated neurodegeneration; (3) Wilson’s disease and related disorders; and (4) other hereditary neurodegenerations without hitherto detected genetic or specific markers. The diversity of phenotypes is related to the deposition of pathologic proteins in distinct cell populations, causing neurodegeneration due to genetic and environmental factors, but there is frequent overlap between various disorders. Their etiopathogenesis is still poorly understood but is suggested to result from an interaction between genetic and environmental factors, multiple etiologies, and noxious factors (protein mishandling, mitochondrial dysfunction, oxidative stress, excitotoxicity, energy failure, chronic neuroinflammation), being more likely than one single factor. Current clinical consensus criteria have increased the diagnostic accuracy of most neurodegenerative movement disorders, but for their definite diagnosis, histopathological confirmation is required. A timely overview of the neuropathology and pathogenesis of the major hyperkinetic movement disorders is presented.

Objective Repeat expansion of polyglutamine tracks leads to a group of inherited human neurodegenerative disorders. Studying such repetitive sequences is required to gain insight into the pathophysiology of these diseases. PCR-based manipulation of repetitive sequences, however, is challenging due to the absence of unique primer binding sites or the generation of non-specific products. Results We have utilised the degeneracy of the genetic code to generate a polyglutamine sequence with low repeat similarity. This strategy allowed us to use conventional PCR to generate multiple constructs with approximately defined numbers of glutamine repeats. We then used these constructs to measure the in vivo variation in autophagic degradation activity related to the different numbers of glutamine repeats, providing an example of their applicability to study repeat expansion diseases. Our simple and easily generalised method of generating low repetition DNA sequences coding for uniform stretches of amino acid residues provides a strategy for generating particular lengths of polyglutamine tracts using standard PCR and cloning protocols.

Telomere molecular biology is far more complex than originally thought. Understanding biological systems is aided by study of evolutionary variants, and Drosophila telomeres are remarkable variants. Drosophila lack telomerase and the arrays of simple repeats generated by telomerase in almost all other organisms; instead, Drosophila telomeres are long tandem arrays of two non-LTR retrotransposons, HeT-A and TART . These are the first transposable elements found to have a bona fide role in cell structure, revealing an unexpected link between telomeres and what is generally considered to be parasitic DNA. In addition to providing insight into the cellular functions performed by telomeres, analysis of HeT-A and TART is providing insight into the evolution of chromosomes, retrotransposons, and retroviruses. Recent studies show that retrotransposon telomeres constitute a robust system for maintaining chromosome ends. These telomeres are now known to predate the separation of extant Drosophila species, allowing ample time for elements and hosts to coevolve interesting mechanisms.

We report on a unified rapid betaine-based-PCR protocol for amplification of the (CAG)n region in Huntington disease (HD) and the (CGG)n region in Fragile X syndrome (FXS), followed by an electrophoretic separation on automated sequencer for precise determination of the triplet numbers. The high betaine concentration (2.5 M betaine) permits precise amplification of the CAG and CGG repeats. Ten HD affected patients and 10 healthy individuals from HD families were re-evaluated. For FXS the CGG region in normal individuals and premutations of about 100 repeats were precisely amplified by this protocol. Ten unrelated FXS premutation carriers and 24 mentally retarded non-FXS affected boys were re-examined by this method. The results totally coincided with the previous ones. This protocol is a good choice as a fast screening test. Within 24 h we can have preliminary information on the patient's genetic status. Normal individuals, CGG premutation carriers up to 100 repeats, as well as HD patients carrying an expansion up to 50 CAG repeats can be easily clarified. This accounts for a relatively large proportion (about 90%) of the suspected HD and FXS patients, referred to our laboratory for genetic analysis. The calculation of the repeat's number is more accurate for the correct interpretation of the results, screening tests and genetic counselling.