Does loss of the normal protein function contribute to the pathogenesis of Huntington's disease?

Paine, Heidi

doi:10.1093/biohorizons/hzv005

Cited by 8 publications

(19 citation statements)

References 38 publications

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“…Several studies have shown that protein aggregation and inclusion formation could contribute to neurodegeneration and disease progression through both gain of toxic function and loss of normal protein function, possibly through aberrant interactions involving protein aggregation or the sequestration of functional proteins within pathological inclusions [50][51][52][53][54] . Therefore, to gain insight into the mechanisms and pathways that are involved and affected by α-syn fibrillization and LB formation and maturation, the list of proteins found enriched in the PFF-treated neurons ( Figure 4A) was further classified by biological processes ( Figure 4C) and signaling pathways ( Figure S8B).…”

Section: Formation and Maturation Of Lb-like Inclusions Are Dynamic Pmentioning

confidence: 99%

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Mahul‐Mellier

Burtscher

Maharjan

et al. 2019

Preprint

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Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LB). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD and synucleinopathies, the processes that govern α-syn fibrillization and LB formation in the brain remain poorly understood. In this work, we sought to reverse engineer LBs and dissect the spatiotemporal events involved in their biogenesis at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we took advantage of a seeding-based model of α-syn fibril formation in primary neurons and further developed this model to generate the first neuronal model that reproduces the key events leading to LB formation; including seeding, fibrillization, and the formation of LB-like inclusions that recapitulate many of the biochemical, structural, and organizational features of LBs found in post-mortem human PD brain tissues. Next, we applied an integrative approach combining confocal and correlative light-electron microscopy (CLEM) imaging methods with biochemical profiling of α-syn species and temporal proteomic and transcriptomic analyses to dissect the molecular events associated with LB formation and maturation and to elucidate their contributions to neuronal dysfunctions and neurodegeneration in PD and synucleinopathies. The results from these studies demonstrate that LB formation involves a complex interplay between α-syn fibrillization, post-translational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria and the autophagosome and endolysosome. Furthermore, we demonstrate that the process of LB formation and maturation, rather than simply fibril formation, is the major driver of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, as well as synaptic dysfunctions. Having a neuronal model that allows for unlinking of the key processes involved in LB formation is crucial for elucidating the molecular and cellular determinants of each process and their contributions to neuronal dysfunction and degeneration in PD and synucleinopathies. Such a model is essential to efforts to identify and investigate the mode of action and toxicity of drug candidates targeting α-syn aggregation and LB formation.

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Section: Formation and Maturation Of Lb-like Inclusions Are Dynamic Pmentioning

confidence: 99%

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Mahul‐Mellier

Burtscher

Maharjan

et al. 2019

Preprint

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“…The median age of diagnosis is around 40 years, with a wide range in age of onset. The expectancy of life after the diagnosis is around 15 to 20 years. , …”

Section: Huntington’s Diseasementioning

confidence: 99%

“…Unlike the other neurodegenerative pathology that has been previously discussed in this review, HD is the only one that presents a precise and defined cause that leads to the onset of this pathology. HD is generated by a genetic mutation of the gene HTT , situated on chromosome 4, that encodes for the huntingtin (Htt) protein. , The pathological gene presents an abnormal number of CAG repeats, which leads to the production of a protein that presents an excessively long polyglutamine stretch near the N-terminus. , This pathology is characterized by different clinical signs, such as progressive motor, behavioral, and cognitive declines. The earliest manifestation of the pathology is usually a general impairment of motor capacity following the appearance of chorea. , This gradually evolves into general rigidity and bradykinesia in late stages.…”

Section: Huntington’s Diseasementioning

confidence: 99%

“…The earliest manifestation of the pathology is usually a general impairment of motor capacity following the appearance of chorea. , This gradually evolves into general rigidity and bradykinesia in late stages. This may be different for those patients who suffer from juvenile HD. , Usually these young patients do not exhibit chorea at the beginning of the pathology, but they directly manifest rigidity and bradykinesia. Generally, concomitant with this motor degeneration, there is a slow but appreciable change of the behavior of the patient who suffers from HD. , Most of these changes appear before the diagnosis, but they are so subtle and progressive that they can be appreciated and defined as a consequence of the pathology only after a certain period.…”

Section: Huntington’s Diseasementioning

confidence: 99%

“…From a biochemical point of view, all the macroscopic manifestations are traceable and attributable to a single gene mutation. The gene responsible for HD is the HTT gene, which displays an abnormal number of CAG repeats in the mutant form. , In a healthy subject, the number of repeats are on average 17 to 20. If the repeats are present in a range between 27 and 35, usually the pathology does not manifest, but those people who present these alterations are more prone to pass an augmented number of repeats to the offspring, due to the higher genetic instability of these subjects.…”

Section: Huntington’s Diseasementioning

confidence: 99%

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The Medicinal Chemistry of Natural and Semisynthetic Compounds against Parkinson’s and Huntington’s Diseases

Zanforlin

Zagotto

Ribaudo

2017

ACS Chem. Neurosci.

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Among the diseases affecting the central nervous system (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients, and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of natural origin that are currently under study against two well-defined pathologies: Parkinson's disease (PD) and Huntington's disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus, and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the etiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semisynthetic compounds dividing them in different paragraphs considering their several mechanisms of action.

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Zebrafish an experimental model of Huntington’s disease: molecular aspects, therapeutic targets and current challenges

Kumar

Singh

2021

Mol Biol Rep

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Does loss of the normal protein function contribute to the pathogenesis of Huntington's disease?

Cited by 8 publications

References 38 publications

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

The Medicinal Chemistry of Natural and Semisynthetic Compounds against Parkinson’s and Huntington’s Diseases

Zebrafish an experimental model of Huntington’s disease: molecular aspects, therapeutic targets and current challenges

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