Collier Lab


Lab Personnel


Aging & Neurodegeneration

The most common human neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease, share the same primary risk factor: aging. A more recent view of this relationship has shifted from aging as an acknowledged risk factor to aging as a fundamental driver of neurodegeneration. Indeed, past work in our laboratory, using a nonhuman primate model of aging, supports the view that the accumulation of pathology characteristic of Parkinson’s disease is recapitulated in aging: not varying in type or location, just magnitude. For Parkinson’s disease, we contend that aging and Parkinson’s exist along the same biological continuum. One potential mechanistic link between aging and neurodegenerative disease is the accumulation of senescent cells in the nervous system. Much of what we know about cellular senescence is derived from study of cells in vitro. In the central nervous system (CNS), the impact of aging-related cell senescence in vivo has been less studied and remains unknown, in part due to the complexity of multiple interactions of cell types exhibiting limited proliferation, including astrocytes, microglia, oligodendrocytes and progenitor cells, and terminally post-mitotic neurons.

To begin to deconstruct the complexity of the interactions of individual classes of CNS cells in aging and age-related neurodegenerative diseases, our laboratory uses viral vector techniques to accelerate aging or decelerate aging, targeted to specific cell types, for effects on pathological hallmarks of aging and neurodegenerative diseases. To achieve this goal, we have become interested in genes and gene products that have been identified to have a direct impact on the course of aging: progerin (“pro-aging”) and klotho (“anti-aging”).  We will use a unique viral vector toolkit to induce cellular aging/senescence (progerin overexpression) or ameliorate cellular aging/senescence (overexpression of klotho), enriched in specific CNS cell types, to examine effects on pathobiology characteristic of aging and neurodegenerative diseases in rat models.

If successful, this project will establish the role of aging as an active driver of neurodegeneration and identify specific CNS cell types as primary participants in this process.

Repurposing Drugs

Parkinson’s disease (PD) is a member of a class of neurodegenerative syndromes termed synucleinopathies, characterized by abnormal accumulations of the protein alpha-synuclein (α-syn) within selectively vulnerable neurons or glial cells. These syndromes are relentlessly progressive with no disease modifying therapy available at present. One reasonable approach to therapy for synucleinopathies is to inhibit accumulation and aggregation of α-syn while maintaining its native states and normal functions. Many strategies have used fibril formation as the indicator that inhibition has been achieved. However, evidence supports the contention that fibrilization is a multi-step process and that fibrils are not in themselves toxic. While prior studies indicate that the process of aggregation initiates from the disordered monomer, it is thought that lower molecular weight oligomers are likely the toxic species. Therefore, inhibition of the formation of toxic α-syn conformations must occur at the earliest stages, perhaps at the monomer level.

However, two main technical hurdles have hampered efforts to find such a therapy. One is incomplete understanding of the earliest stages of aggregation. Our collaborator, Dr. Lisa Lapidus in the physics department at Michigan State, has developed a model for the first step of aggregation and has documented that observing the rate of reconfiguration of the unstructured monomer accurately predicts aggregation propensity. This technique can be used to test whether drug candidates prevent aggregation at the earliest stage. A second technical hurdle is the ability to test such drug candidates in live animals that are good models of PD. Our group has developed and characterized a rat model of PD that significantly improves on earlier animal models by incorporating the alpha-synuclein (α-syn) pathology characteristic of human PD. The collaboration in this project has the unique ability to test whether PD drug candidates can keep α-syn monomeric in vitro and also prevent aggregation and dopamine neuron degeneration in live animals. A drug candidate that is successful in both stages of testing is then ready for consideration for clinical trials. One notable success with our combined in vitro-in vivo approach to drug discovery is the tricyclic antidepressant medication nortriptyline that exhibits potent α-syn anti-aggregation effects in both assays.

If successful, this project will identify additional compounds to further validate the utility of the combined approach in identifying compounds with the potential to interfere with development and progression of α-syn pathology and serve as disease-modifying interventions for PD and other synucleinopathies.

Circadian Disruption in PD

Increasing attention is being paid to the non-motor features of Parkinson’s disease (PD) as primary contributors to poor quality of life. An emerging area of interest is the contribution of circadian rhythms to several features of PD. These 24-hour oscillations in behavior, physiology and gene expression appear to be powerfully linked to PD and include altered diurnal fluctuations in motor symptoms, indicators of autonomic function, sleep disruption, and expression of circadian clock genes.  Circadian disruption also is detectable in toxin and transgenic animal models of parkinsonism.  Our review of the literature leads us to four conclusions: 1) Circadian disruption is common to many of the non-motor features of PD and often are detectable prior to the emergence of motor symptoms. 2) Animal models of PD exhibit disruption of circadian rhythms. 3) Many of the mechanisms associated with PD neurodegeneration including autophagy, oxidative stress, DNA repair and neuroinflammation either show circadian oscillation or are subject to alterations produced by circadian disruption. 4) While the association of circadian disruption with parkinsonism is established, the role of circadian disruption as a contributor to parkinson’s pathogenesis, including a-syn pathology, has not.

In this project we examine the potential for circadian rhythm disruption to act as a contributor to the progression of synucleinopathy relevant to PD.  We test this interaction using the rat a-syn pre-formed fibril (PFF) injection model.  Features of this model allow analysis of the progression of synucleinopathy distinct from the later events associated with neurodegeneration.  To produce circadian rhythm disruption we use the chronic light-dark cycle shift paradigm.  This paradigm has been shown to be 100% effective in desynchronizing circadian rhythms in rodents in a reliable and highly reproducible manner.

If the findings support the contention that rhythm disruption contributes to the magnitude and/or rate of a-syn pathogenesis and neurodegeneration, it provides a target that is accessible and modifiable by environmental interventions that have the potential to slow the progression of PD.