Mitochondrial biology and the identification of biomarkers of Huntington's disease

2020 ◽  
Vol 10 (4) ◽  
pp. 243-255
Author(s):  
Andreas Neueder ◽  
Michael Orth
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Biological Processes ◽  
Protein Species ◽  
Mitochondrial Quality Control ◽  
The Core ◽  
Core Elements ◽  
Human Material ◽  
Important Challenge

Apart from finding novel compounds for treating Huntington's disease (HD) an important challenge at present consists in finding reliable read-outs or biomarkers that reflect key biological processes involved in HD pathogenesis. The core elements of HD biology, for example, HTT RNA levels or protein species can serve as biomarker, as could measures from biological systems or pathways in which Huntingtin plays an important role. Here we review the evidence for the involvement of mitochondrial biology in HD. The most consistent findings pertain to mitochondrial quality control, for example, fission/fusion. However, a convincing mitochondrial signature with biomarker potential is yet to emerge. This requires more research including in peripheral sources of human material, such as blood, or skeletal muscle.

scholarly journals Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex

2021 ◽  
pp. 1-13
Author(s):  
Karen A. Sap ◽  
Arzu Tugce Guler ◽  
Aleksandra Bury ◽  
Dick Dekkers ◽  
Jeroen A.A. Demmers ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Cortex ◽  
Full Length ◽  
Biological Processes ◽  
Interacting Proteins ◽  
Mutant Huntingtin ◽  
Wild Type ◽  
Mutant Huntingtin Protein ◽  
Mice Brain

Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

scholarly journals Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington's disease

2022 ◽  
Author(s):  
Sanzana Hoque ◽  
Marie Sjogren ◽  
Valerie Allamand ◽  
Kinga Gawlik ◽  
Naomi Franke ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Muscle Damage ◽  
Satellite Cell ◽  
Mouse Models ◽  
Satellite Cells ◽  
Muscle Fibers ◽  
Cag Repeat ◽  
Skeletal Muscle Regeneration

Huntington's disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise. In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice. We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage. Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.

scholarly journals Mechanisms of altered skeletal muscle action potentials in the R6/2 mouse model of Huntington’s disease

2020 ◽  
Vol 319 (1) ◽  
pp. C218-C232 ◽  
Author(s):  
Daniel R. Miranda ◽  
Eric Reed ◽  
Abdulrahman Jama ◽  
Michael Bottomley ◽  
Hongmei Ren ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Decay Time ◽  
Motor Dysfunction ◽  
Peak Amplitude ◽  
Repetitive Firing ◽  
Muscle Pathology ◽  
Mrna Levels ◽  
Electrode Current

Huntington’s disease (HD) patients suffer from progressive and debilitating motor dysfunction for which only palliative treatment is currently available. Previously, we discovered reduced skeletal muscle Cl− channel (ClC-1) and inwardly rectifying K+ channel (Kir) currents in R6/2 HD transgenic mice. To further investigate the role of ClC-1 and Kir currents in HD skeletal muscle pathology, we measured the effect of reduced ClC-1 and Kir currents on action potential (AP) repetitive firing in R6/2 mice using a two-electrode current clamp. We found that R6/2 APs had a significantly lower peak amplitude, depolarized maximum repolarization, and prolonged decay time compared with wild type (WT). Of these differences, only the maximum repolarization was accounted for by the reduction in ClC-1 and Kir currents, indicating the presence of additional ion channel defects. We found that both KV1.5 and KV3.4 mRNA levels were significantly reduced in R6/2 skeletal muscle compared with WT, which explains the prolonged decay time of R6/2 APs. Overall, we found that APs in WT and R6/2 muscle significantly and progressively change during activity to maintain peak amplitude despite buildup of Na+ channel inactivation. Even with this resilience, the persistently reduced peak amplitude of R6/2 APs is expected to result in earlier fatigue and may help explain the motor impersistence experienced by HD patients. This work lays the foundation to link electrical changes to force generation defects in R6/2 HD mice and to examine the regulatory events controlling APs in WT muscle.

Skeletal muscle characteristics and mitochondrial function in Huntington's disease patients

2017 ◽  
Vol 32 (8) ◽  
pp. 1258-1259 ◽  
Author(s):  
Saskia Maria Gehrig ◽  
Jens A. Petersen ◽  
Sebastian Frese ◽  
Sandro Manuel Mueller ◽  
Violeta Mihaylova ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mitochondrial Function

scholarly journals Deterioration of mitochondrial bioenergetics and ultrastructure impairment in skeletal muscle of a transgenic minipig model in the early stages of Huntington's disease

2019 ◽  
Vol 12 (7) ◽  
pp. dmm038737 ◽  
Author(s):  
Marie Rodinova ◽  
Jana Krizova ◽  
Hana Stufkova ◽  
Bozena Bohuslavova ◽  
Georgina Askeland ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mitochondrial Bioenergetics ◽  
Early Stages

scholarly journals Altered Ca2+ signaling in skeletal muscle fibers of the R6/2 mouse, a model of Huntington’s disease

2014 ◽  
Vol 144 (5) ◽  
pp. 393-413 ◽  
Author(s):  
Peter Braubach ◽  
Murat Orynbayev ◽  
Zoita Andronache ◽  
Tanja Hering ◽  
Georg Bernhard Landwehrmeyer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Voltage Clamp ◽  
Trinucleotide Repeat ◽  
Transport Model ◽  
Muscle Fibers ◽  
Muscle Pathology ◽  
Release Flux ◽  
Inward Currents

Huntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat within the gene encoding the protein huntingtin. The resulting elongated glutamine (poly-Q) sequence of mutant huntingtin (mhtt) affects both central neurons and skeletal muscle. Recent reports suggest that ryanodine receptor–based Ca2+ signaling, which is crucial for skeletal muscle excitation–contraction coupling (ECC), is changed by mhtt in HD neurons. Consequently, we searched for alterations of ECC in muscle fibers of the R6/2 mouse, a mouse model of HD. We performed fluorometric recordings of action potentials (APs) and cellular Ca2+ transients on intact isolated toe muscle fibers (musculi interossei), and measured L-type Ca2+ inward currents on internally dialyzed fibers under voltage-clamp conditions. Both APs and AP-triggered Ca2+ transients showed slower kinetics in R6/2 fibers than in fibers from wild-type mice. Ca2+ removal from the myoplasm and Ca2+ release flux from the sarcoplasmic reticulum were characterized using a Ca2+ binding and transport model, which indicated a significant reduction in slow Ca2+ removal activity and Ca2+ release flux both after APs and under voltage-clamp conditions. In addition, the voltage-clamp experiments showed a highly significant decrease in L-type Ca2+ channel conductance. These results indicate profound changes of Ca2+ turnover in skeletal muscle of R6/2 mice and suggest that these changes may be associated with muscle pathology in HD.

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