Understanding the role of DNA damage response in neurodegeneration

The Balmus Laboratory is interested in understanding the roles of DNA Damage Response (DDR) in mature neurons and its links to neurodegenerative disorders (including Alzheimer’s and related diseases) and aging.  

We are using a variety of tools including CRISPR-Cas9 screens in mature neurons as well as mouse models of disease.  

While maintenance of genome stability is important for all cells and has been implicated in an array of pathologies, it is critical for the terminally differentiated neuron that has no other way of protecting its genetic material but through repair. As such, the bulk of DDR syndromes present neurological features and loss of DDR pathway regulation is one of the first events in the ageing brain.

Dopamine neurons (green) in a milieu of cortical neurons (red)

In the Balmus  Laboratory we are interested in understanding the mechanisms by which neurons deal with endogenous genotoxic stresses, their contribution to progression of neurodegeneration and ageing, and how to harness this knowledge to inform on key nodes that can be targeted to confer protection.

“We totally missed the possible role of ... [DNA] repair although ... I later came to realise that DNA is so precious that probably many distinct repair mechanisms would exist.” Francis Crick, writing in Nature, 26 April 1974

Huntington’s Disease

Huntington’s Disease (HD) is a fatal autosomal dominant neurodegenerative disease caused by unstable expansion of a CAG triple nucleotide repeat in the coding region of the HTT gene. Currently there is no treatment that can slow or stop disease initiation or progression, thus there is an unmet need for research aimed at discovering disease modifiers prospective to become used in therapy. Large HD population studies have recently uncovered that the expansion of repeats is strongly modified by a set of factors involved in repairing DNA damage, thus critical for genome maintenance. In the Lab we are using CRISPR/Cas9 across the whole class of known DNA damage and/or DNA repair response genes to explore their impact on repeat expansion or contraction in human induced pluripotent cell lines derived from HD patients as well as established mouse embryonic stem cell HD models. Working alongside our strong collaborators in Prof Sarah Tabrizi Laboratory in London we hope to identify the exact network of DNA damage repair responsive genes that can positively or negatively regulate repeat expansion in HD. This has enormous importance for devising new interventions, both for diagnostic or therapeutic use, as well as for repurposing drugs. 

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are difficult to diagnose and with no effective treatment available.  Recent evidence started to emerge for genomic instability as an important contribution in ALS and FTD.  At close inspection it has been shown that ALS neurons accumulate toxic double strand breaks (DSBs).  That being said is not very clear what type of endogenous stress is responsible for the build-up of DSBs and what is the exact mechanism of action.  We have shown in the past that members of the DSB repair pathways behave differently depending of the replication status and cell types starting to point more and more to a re-wiring of DDR in neurons as compared to replicating cell types.  This requires for comparative analyses between replicating vs. non-replicating neurons in ALS deficient backgrounds as paralleled to the normal wild-type scenario.  Further investigation along these lines may add new dimensions to our knowledge of genome repair and their defects in neurodegenerative diseases and will allow us to develop clinically effective strategies to ameliorate genome instability ALS.

Ataxia Telangiectasia

Ataxia Telangiectasia (AT) is mainly a neurodegenerative disease that occurs in early-childhood with onset of ataxia due to premature degeneration of neuro-cerebellar cells. While in the last 23 years since ATM discovery we made enormous leaps in understanding the role of ATM in cancer/replicating cells, little have we learned about the specific roles of ATM in neurons. Outside of the cerebellum ATM has been reported to be involved in late-onset degenerative disease such as Alzheimer’s Disease as well as ALS. This raises the possibility that mechanisms similar to those in neuro-cerebellar cells are present in other neurons such as cortical neurons but the late-onset degeneration in dementias (after age 50) makes such clinical presentations rare (but not unseen) in AT. In order to address the ongoing debate, in our Laboratory we are developing new neuronal models that can be used to dissect the role of ATM in maintaining genomic stability in neurons and to ask what are the roles of ATM in responding to endogenous damages such as oxidative damage. Understanding these basic molecular functions will allow us to establish robust assays that in combination with CRISPR-Cas9 whole-genome screens will identify disease-modifying suppressors.

Parkinson’s Disease

Parkinson’s disease (PD) is a devastating condition that affects approximately 1- 2% of the population over the age of 65 years and that is thought to increase in incidence in the following decades.  Out of the total number of PD patients 10% to 15% of cases are caused by mutations in the genes LRRK2, PINK1, PRKN, SNCA or PARK7 representing familial cases of PD.  Understanding the role of these genes in PD has provided great insights into the molecular mechanisms of disease onset and progression and raised the possibility that the functions of the affected genes might overlap or interact through common pathways.  It is thus thought that the loss of dopamine neurons in the substantia nigra in PD is mainly due to increased sensitivity to oxidative stress upon metabolic reactive oxygen species (ROS) production, alpha-synuclein accumulation, as well as upon mitochondrial dysfunction. In the Laboratory we are exploring how increased ROS, but also other reactive species, leads to increased neuronal cell death by exploring the mechanisms required to maintain genomic and mitochondrial stability under increased endogenous damage.