1. MITOCHONDRIA AND HUNTINGTON'S DISEASE
By: Mustafa Mohammed Ahmed
Uswa Ashir Yazdani
Avneet Bahia
Riya Patel
October 17th 2017
PHM Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson

2. WHAT IS MITOCHONDRIA? “Powerhouse” of the cell
Membrane bound organelle
Function: generate large quantities of energy in the form of ATP (energy metabolism), store calcium for cell signaling activities (calcium homeostasis), generate heat, and mediate cell growth and death
Central component of apoptosis (programmed cell death)

3. WHAT IS HUNTINGTON’S DISEASE?
Genetic, autosomal dominant neurodegenerative disorder
Underlying mutation is CAG trinucleotide repeat expansion within exon 1 of the Huntingtin protein
Results in changes to the structural properties and functional activities of the Huntingtin protein due to an expanded polyglutamine tract
Effects: cognitive deficits, loss of motor coordination, psychiatric disruption, inability to make decisions, control emotions and recall events

5. WHY IS IT DANGEROUS ? Elongated protein is cleaved into smaller pieces
Fragments bind together, accumulate in neurons
Mutant Htt protein binds to proteins involved in transcription, cell cycle, energy metabolism and cell signalling
These interactions influence cellular processes which can cause cell death and apoptosis
Leads to eventual cell death
Neuronal degradation which can lead to death

6. HOW ARE THEY RELATED?
Huntingtin protein is expressed in different cellular compartments such as the cytosol, nucleus and mitochondria
Mitochondrial defects and oxidative stress have been detected in biological materials from patients with neurodegenerative disorders
o Mitochondria play an active role in the cascade of events resulting in cell death in models of neurodegenerative disorders

7. HOW ARE THEY RELATED?
Mitochondria expressing mutant huntingtin protein have :
decreased membrane potential
decreased expression of oxidative phosphorylation enzymes
high ROS levels
increased apoptosis
decreased succinate dehydrogenase activity, which is a component of the electron transport chain (ETC) and tricarboxylic acid Krebs cycle
low ATP generation

8. EVIDENCE Mitochondrial function impaired in animal and cell models
Showed selective lesioning of the striatum when used 3-NP (3-nitropropionic acid), an irreversible inhibitor of succinate dehydrogenase, in animal and human models
When chronically administered low 3-NP to rodents and primates, specific lesions in striatum with selective vulnerability of medium-sized spiny neurons was observed as seen in HD patients.
Reduced membrane potential in mice

9. Calcium dysfunction in HD
NMDAR - NMDA receptor
InsP3 R1- inositol triphosphate receptor 1
mtPTP - mitochondrial permeability transition
pore

10. PHARMACEUTICAL THERAPEUTICS
There is no direct medication/therapy for HD
Antidopaminergic agents (Tetrabenzine -TBZ)
- Improved Mean Chorea scores
2) Antipsychotic agents ( Haloperidol, Colazapine )
- Reduced involuntary movements

11. FUTURE TREATMENTS
Gene Silencing ?

12. SUMMARY
Mitochondria is responsible for energy metabolism, calcium homeostasis, heat generation and takes part in cell growth and death
Huntington’s disease is a neurodegenerative disease which results from a mutation in the gene encoding for Huntingtin protein
The mutation is a CAG trinucleotide expansion
Mitochondria in individuals with Huntington’s disease has decreased membrane potential, increased apoptosis and low ATP generation due to interruptions in energy metabolism
Huntington’s disease causes calcium dysregulation, which leads to cell death and neurodegeneration
No known cure for Huntington’s Disease

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