Huntington’s disease, a neurodegenerative condition often associated with older adults, typically manifests around the age of 40. It presents with motor symptoms such as involuntary movements and impaired coordination, along with cognitive challenges like memory loss and attention deficits, and psychiatric issues including depression, irritability, psychosis, and anxiety.
The disease stems from the misfolding of the protein encoded by a mutated huntingtin gene (HTT). This misfolded protein adversely impacts physiological neuronal function, including transcription, protein degradation, folding, and mitochondrial function, disrupting neuronal circuitry.
Transcriptional dysregulation is a primary consequence of mutant huntingtin protein (mHTT) in HD. mHTT interferes with transcription factors and co-regulators, causing widespread changes in gene expression.
Heat Shock Factor 1 (HSF1) is the master regulator of the heat shock response. Its inhibition by aggregated mHTT exacerbates protein misfolding and aggregation. mHTT also interacts with CREB-binding protein (CBP) and p300, hindering their role in gene transcription. Additionally, mHTT binds to P300/CBP-Associated Factor (PCAF), inhibiting its activity and further repressing essential genes. Sp1 plays an important role in the regulation of the human huntingtin gene, and increased Sp1 expression contributes to the pathology of HD.
The interplay between protein folding and degradation is crucial for maintaining cellular homeostasis. In HD, the overwhelming presence of misfolded mHTT disrupts protein folding and degradation pathways, leading to toxic protein aggregates and neuronal death.
HSP70, a crucial molecular chaperone, assists in nascent protein folding as well as refolding of misfolded proteins. In HD, misfolded mHTT overwhelms HSP70, limiting its capacity to manage protein folding and resulting in toxic aggregates. Furthermore, misfolded mTT hampers DNAJ proteins (HSP40) which act as co-chaperones to HSP70.
CHIP, an E3 ubiquitin ligase, tags misfolded proteins for degradation via the ubiquitin-proteasome system. mHTT disrupts CHIP function, reducing ubiquitination efficiency and leading to toxic protein aggregates. Ubiquitin itself is also affected as mHTT disrupts the ubiquitination process, leading to the buildup of non-degraded ubiquitinated proteins. The proteasome, responsible for degrading ubiquitinated proteins, is compromised by the accumulation of misfolded proteins, further exacerbating cellular toxicity.
Sequestosome-1 (p62/SQSTM1) directs ubiquitinated proteins to autophagosomes for degradation but in HD is sequestered into mHTT aggregates, impairing its function. Autophagosomes, which engulf damaged proteins and organelles for lysosomal degradation, are disrupted by mHTT, impairing autophagy and increasing protein aggregate levels.
mHTT disrupts various mitochondrial functions, leading to neuronal energy deficits, increased oxidative stress, and cell death which contributes significantly to HD progression.
PGC-1α, a master regulator of mitochondrial biogenesis and function, promotes the expression of genes involved in mitochondrial respiration and antioxidant defense. In HD, mHTT represses PGC-1α activity, resulting in diminished energy production and increased oxidative damage. mTT also disrupts the electron transport chain, impairing electron transport and reducing ATP synthesis. This dysfunction leads to the leakage of electrons and increased reactive oxygen species production, causing oxidative stress that damages mitochondrial DNA, proteins, and lipids. This exacerbates mitochondrial dysfunction further, creating a vicious cycle.
Mitochondrial fusion – involving proteins like Mitofusin 1, Mitofusin 2, and Optic Atrophy 1– maintains mitochondrial function by mixing contents of partially damaged mitochondria. mHTT disrupts these fusion proteins, leading to fragmented, dysfunctional mitochondria and impaired mitochondrial networks.
Proper mitochondrial distribution within neurons, facilitated by motor proteins like kinesin and dynein, is crucial for meeting localized energy demands. mHTT interferes with mitochondrial transport by disrupting the interaction between mitochondria and motor proteins, leading to damaged mitochondria accumulation in the cell body and a shortage of functional mitochondria at synaptic sites, contributing to synaptic dysfunction and neuronal degeneration.
The combined effects of mHTT on PGC-1α, mitochondrial complexes, ROS generation, mitochondrial fusion, and transport culminate in neuronal energy deficits, increased oxidative stress, and cell death.
The progressive loss of neurons and synaptic dysfunction in HD causes disrupted neuronal circuitry. mHTT affects key neurotransmitters and their receptors, disrupting normal neuronal communication.
Brain-Derived Neurotrophic Factor (BDNF) is crucial for neuronal survival, synaptic plasticity, and function. mHTT reduces BDNF transcription and transport, impairing neuronal function and increasing vulnerability to degeneration. Additionally, mHTT affects Tropomyosin Receptor Kinase B (TrkB) signaling, further compromising neuronal survival.
Dopamine release and receptor function is also disrupted by mHTT, affecting motor control and reward pathways. Dopamine Receptor D2 (DRD2) expression and function are reduced, leading to impaired dopamine signaling and contributing to motor dysfunction and psychiatric symptoms.
Glutamate, the primary excitatory neurotransmitter essential for synaptic plasticity and cognitive functions, is increased by mHTT, impairing its reuptake and leading to excitotoxicity. NMDA receptor activity is enhanced by mHTT, causing increased calcium influx. This excitotoxicity damages and kills neurons, further disrupting neuronal circuits.
The disruption of BDNF, dopamine, and glutamate release, along with their receptor impairments, contributes to the breakdown of neuronal circuitry in HD, leading to motor, cognitive, and psychiatric symptoms.
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