Sussex Neuroscience

Dr Majid Hafezparast

Majid

Mechanisms of neurodegenerative disease.

Neurodegenerative diseases consist of a large, varied group of pathologies, characterised by the degeneration of specific subsets of neurons and they include pathologies often seen in the elderly. In Alzheimer’s disease (AD), Parkinson’s disease (PD) and Motor Neurone Diseases (MND) such as Amyotrophic Lateral Sclerosis (ALS), the average onset age is over 50. With an ever-increasingly aging population in Western countries, the socio-economic cost is rising as neurodegenerative diseases affect more people. In the UK alone it is estimated that by the end of 2015 there will be over 850,000 people with dementia, including AD, and 127,000 people with PD. Moreover, MNDs affect 2 in 100,000 people with a lifetime risk of 1 in 500 in women and 1 in 350 in men in the UK. ALS, the most common form of adult-onset MND, kills within 2-5 years after appearance of the symptoms.
All above mentioned diseases are progressive neurodegenerative disorders that exhibit axonal pathologies, including accumulation of cargoes such as proteins and organelles in axons, indicating dysfunction of axonal transport. Axonal transport could be disrupted via a number of mechanisms, such as dysfunction of molecular motors that transport organelles and signalling molecules, and damage to the microtubules tracks thereby disrupting movement of the molecular motors. Neurons are equipped with two quality control systems namely autophagy and ubiquitin proteasome system (UPS) for clearance of damaged organelles and proteins. Importantly, failure in this process leads to accumulation of misfolded proteins and formation of pathological inclusion bodies characteristic of the neurons affected in AD, PD, or MND. Cytoplasmic dynein is the motor protein responsible for the retrograde transport and delivery of autophagosomes, the double-membrane organelles that engulf cellular cargo destined for clearance via autophagy, to the perinuclearly located lysosomes. The autophagic contents are then broken down by an array of lysosomal enzymes. Thus dynein-mediated transport is crucial for delivering damaged organelles and proteins to the lysosomes and ensuring healthy cellular homeostasis. Interestingly, impaired axonal transport is one of the earliest manifestations of adult-onset neurodegenerative diseases. This has raised an important and yet unanswered question: Could a reduction in dynein-mediated axonal transport be a primary cause of accumulation of toxic misfolded proteins, leading to development of any of the age-related neurodegenerative diseases?
We seek to answer this longstanding question. Our hypothesis is that age-related reduction in dynein function and/or hypomorphic variations in the core component of dynein, cytoplasmic dynein heavy chain 1 (DYNC1H1), predispose neurons to dysfunctional protein degradation and consequently accumulation of toxic protein aggregates, leading to neuronal cell death in neurodegenerative diseases.

This PhD project will use cell and molecular biology techniques in combination with high-resolution microscopy to test the above hypothesis and establish whether reduced axonal transport causes accumulation and aggregation of toxic misfolded proteins in two neuronal cell populations namely cholinergic and dopaminergic neurons, which are the primary targets of AD, MND, and PD.

Selected publications:

(For full list of publications and more details about the lab, please visit: http://www.sussex.ac.uk/lifesci/hafezparastlab/)

1] Trott L, Hafezparast M, Madzvamuse A. A mathematical understanding of how
cytoplasmic dynein walks on microtubules. R Soc Open Sci. 2018 Aug 8;5(8):171568.
doi: 10.1098/rsos.171568. eCollection 2018 Aug. PubMed PMID: 30224978; PubMed
Central PMCID: PMC6124060.

2] De Vos KJ, Hafezparast M. Neurobiology of axonal transport defects in motor
neuron diseases: Opportunities for translational research? Neurobiol Dis. 2017
Sep;105:283-299. doi: 10.1016/j.nbd.2017.02.004. Epub 2017 Feb 22. Review. PubMed
PMID: 28235672; PubMed Central PMCID: PMC5536153.

3] Garrett CA, Barri M, Kuta A, Soura V, Deng W, Fisher EM, Schiavo G,
Hafezparast M. DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos
signalling in a mouse model of distal spinal muscular atrophy. Brain. 2014
Jul;137(Pt 7):1883-93. doi: 10.1093/brain/awu097. Epub 2014 Apr 22. PubMed PMID:
24755273.

4] Schiavo G, Greensmith L, Hafezparast M, Fisher EM. Cytoplasmic dynein heavy
chain: the servant of many masters. Trends Neurosci. 2013 Nov;36(11):641-51. doi:
10.1016/j.tins.2013.08.001. Epub 2013 Sep 10. Review. PubMed PMID: 24035135;
PubMed Central PMCID: PMC3824068.

5] Oates EC, Rossor AM, Hafezparast M, et al.
Mutations in BICD2 cause dominant congenital spinal muscular atrophy and
hereditary spastic paraplegia. Am J Hum Genet. 2013 Jun 6;92(6):965-73. doi:
10.1016/j.ajhg.2013.04.018. Epub 2013 May 9. PubMed PMID: 23664120; PubMed
Central PMCID: PMC3675232.

6] Deng W, Garrett C, Dombert B, Soura V, Banks G, Fisher EM, van der Brug MP,
Hafezparast M. Neurodegenerative mutation in cytoplasmic dynein alters its
organization and dynein-dynactin and dynein-kinesin interactions. J Biol Chem.
2010 Dec 17;285(51):39922-34. doi: 10.1074/jbc.M110.178087. Epub 2010 Oct 2.
PubMed PMID: 20889981; PubMed Central PMCID: PMC3000974.

7] El-Kadi AM, Bros-Facer V, Deng W, Philpott A, Stoddart E, Banks G, Jackson GS,
Fisher EM, Duchen MR, Greensmith L, Moore AL, Hafezparast M. The legs at odd
angles (Loa) mutation in cytoplasmic dynein ameliorates mitochondrial function in
SOD1G93A mouse model for motor neuron disease. J Biol Chem. 2010 Jun
11;285(24):18627-39. doi: 10.1074/jbc.M110.129320. Epub 2010 Apr 9. PubMed PMID:
20382740; PubMed Central PMCID: PMC2881788.

8] Hafezparast M, Klocke R, Ruhrberg C, et al. Mutations in dynein link motor neuron
degeneration to defects in retrograde transport. Science. 2003 May
2;300(5620):808-12. PubMed PMID: 12730604.