By

Janani V (1807025)
Huntington disease

● Huntington’s disease is a progressive neurodegenerative disorder that

exhibits a dominant pattern of inheritance (50%).
● It is most prevalent in people of Western European descent (more than 15
incidences per 100,000 people).
● It usually strikes affected individuals during the fourth decade of life (40
years).
● It is characterized by abnormal movement, cognitive impairment, mood
disorders, and behavioral changes. The disorder ultimately leads to death
(usually 15-18 years after onset of symptoms).
Genetics and Pathology of Huntington’s Disease

● Huntington’s disease is an autosomal dominant disease with a 100%

phenotypic penetrance.
● It is a result of a mutation of the HTT gene on chromosome 4, which codes
for a protein that is important during the early neuronal development of the
human fetusThe product of the HTT gene is called huntingtin.
● Though the exact role is still unknown, within cells, the gene and its
associated product are known to be involved in chemical signaling,
transporting materials, attaching to proteins, and protecting the cell from
self-destruction.
● Huntington's disease is a “trinucleotide repeat mutation disorder”. • Under
normal conditions, HTT gene has a certain number of CAG repeats. • Under
abnormal conditions, the number of CAG repeats is increased significantly.
cont….
● Normal Number of CAG Repeats: fewer than 26 ,Intermediate Num. of
Repeats: 27-35 (Meiotic ally Unstable in Males) HD-causing : 36 and more
(can go as high up as 120 repeats!!!)
● The extra repeats result in the gene abnormality, which in turn results in a
misshapen version of the huntingtin protein in the area of Exon 1.
● The elongated protein is cut into smaller, toxic fragments that bind
together and accumulate in neurons, disrupting their normal functions.
● This process particularly affects regions of the brain that help coordinate
movement and control thinking and emotions (the striatum, Globus
pallidum and cerebral cortex).
Post‑translational modifications of HTT/mutHTT

HTT is also likely modified by phosphorylation, SUMOylation, acetylation and

palmitoylation and these post-translational modifications are important in proper
protein‑protein interactions of HTT, which can be significantly altered by
mutations and polyQ additions .
Histone acetyltransferase (HAT) enzymes CBP and PCAF were found to be
inactivated by mutHTT through protein-protein interactions, leading to
transcriptional and chromatin remodeling deregulation and contributing to the
pathogenesis of HD
Therapeutic approaches
Conventional treatment

Dopamine antagonists are used to supress movement disorders and behavioural

abnormalities

The aim of the therapy is to mask the symptoms of disease progression. • The abnormal
movements (chorea) can be controlled with antipsychotic agents (Haloperidol) and muscle
relaxants (benzodiazepines).substance block dopamine receptor include (reserpine ,dozapine
and tetrabenazine)
Potential pathological molecular events in Huntington's disease and possible
therapeutic interventions.
Cont ..
● Due to the interaction-mediated inhibitory effects of mutHTT on HAT enzymes,
certain inhibitors of histone deacetylases (HDAC), in particular HDAC4, have been
examined for their protective effects in some models of HD. The findings showed
that these inhibitors were able to reduce the aggregation of mutHTT and also rescue
the neuronal and corticostriatal synaptic function.
● Another important HD pathology-associated change is in the cyclic AMP (cAMP)
signaling and aberrant transcription of genes regulated by the cAMP response
element (CREB) with cell culture models its demonstrated over expression of
CREB protein reduce the influence of polyglutamine expanded protein .
● Another approach is to modulate Huntington protein activity huntington
mutation is associated with reduction in brain derived neurotrophic factor
restoration of wild type huntington via gene transfer enhances the expression
of brain derived neurotrophic factor Inhibition of transcription by zinc finger
proteins (ZFPs) were used to reduce the transcription from the HTT gene
● Another approach to lower the expression of mutHTT is to target the
corresponding mRNA with specific antisense oligonucleotides (ASOs)This
ASO-induced restoration of normal functionality was sustained even after the
infused ASOs were removed, indicating that there was a restoration and
recovery of the neurons rendered dysfunctional due to mutHTT
Emerging therapies for Huntington's disease. ASO, antisense
oligonucleotides; HTT, huntingtin
References
● Huang WJ, Chen WW, Zhang X. Huntington's disease: Molecular basis of pathology and
status of current therapeutic approaches. Exp Ther Med. 2016;12(4):1951-1956.
doi:10.3892/etm.2016.3566
● Bioregenerative Engineering: Principles and Applications Liu, Shu Q.Published by
Wiley-Interscience, 2007ISBN 10: 0471709077ISBN 13: 9780471709077