The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing.
Our data unveil mitochondrial dysfunction as a contributor to the impaired dendritic maturation of FMRP-deficient neurons and suggest a role for interactions between FMRP and HTT in the pathogenesis of fragile X syndrome.
One of the problems arising from the misfolded Huntingtin is the increase in oxidative stress, which is common to many neurological diseases such as Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis and Creutzfeldt-Jakob disease.
These findings suggest that trans-neuronal diffusion of mutant huntingtin protein across the human brain connectome may explain the pattern of gray matter degeneration and white matter disconnection that are hallmarks of HD.
In human amyloid precursor protein transgenic Tg2576 mice with amyloid plaque pathology, similar neuronal HTT expression patterns and a distinct association of HTT with Abeta plaques were revealed by immunohistochemical double labelling.
Huntington's disease (HD) is classified as a protein-misfolding disease correlated with the mutant Huntingtin (mHtt) protein with abnormally expanded polyglutamine (polyQ) domains.
Multiple pleiotropic gene variants can alter risk for Tau or TDP-43 pathologies, and certain gene variants (e.g., APOE ε4, Huntingtin triplet repeats) are associated with increases of both Tau and TDP-43 proteinopathies.
In human amyloid precursor protein transgenic Tg2576 mice with amyloid plaque pathology, similar neuronal HTT expression patterns and a distinct association of HTT with Abeta plaques were revealed by immunohistochemical double labelling.
We used clinical similar transgenic HD mice carrying a mutant HTT exon 1 containing 84 CAG trinucleotide repeats to evaluate the relationship between HD and pain.
Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD.
Early metabolic impairment at least in part associated with mitochondrial complex II deficiency may play a key role in huntingtin-induced mechanisms of neurodegeneration.
Moreover, polyQ-expanded Htt-N552 and Atx-3 reduce the protein level of xeroderma pigmentosum group C (XPC) by sequestration of hHR23B, suggesting that this process may cut down the available quantity of hHR23B and thus affect its normal function in stabilizing XPC.
Finally, the HTT Interactome highly intersects protein networks of pathogenic genes underlying Parkinson's, Alzheimer's and eight non-HD polyglutamine diseases, ALS, and spinal muscular atrophy.
We found that high baseline BMI was associated with a significantly slower rate of functional, motor, and cognitive deterioration (all p < 0.001), independent of mutant HTT CAG repeat size.
Support for this thesis is based on these observations: (1) heat shock induces improvements in synapse integrity and memory consolidation; (2) synaptic depolarization activates HSF1; (3) activation of HSF1 alone (independent of the canonical heat shock response) augments formation of essential synaptic elements-neuroligands, vesicle transport, synaptic scaffolding proteins, lipid rafts, synaptic spines, and axodendritic synapses; (4) HSF1 coalesces and activates memory receptors in the post-synaptic dendritic spine; (5) huntingtin or α-synuclein accumulation lowers HSF1 while HSF1 lowers huntingtin and α-synuclein aggregation-a potential vicious cycle; and (6) HSF1 agonists (including physical activity) can improve cognitive function in dementia models.
The abnormal expansion of a ≥36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD-causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer.