Neurodegenerative disorders are proteinopathic conditions arising from the misfolding and aggregation of specific proteins. There are no treatments that prevent the formation of these aggregations; currently available therapies only mask the neurological symptoms. However, all cells contain chaperones that can prevent protein misfolding and aggregation or clear damaged proteins through multiple waste disposal systems. The major stress-responsive chaperone in all cells is the abundant heat shock protein 70 (Hsp70), a potent neuroprotectant. However, delivery of Hsp70 to the brain is challenging because of the blood-brain barrier. We propose to overcome this barrier by infusing Hsp70 into the nose in a novel mouse model of Lewy body disorders. Intranasal delivery allows many proteins to bypass the blood-brain barrier and avoids metabolism in the liver. Evidence has also accumulated suggesting that the pathology of Lewy body disorders partly commences in the olfactory system, from where it may be transmitted cell-to-cell through neuroanatomical circuitry deep into the brain as clinical symptoms are magnified. We have modeled the spread of alpha-synuclein pathology in Lewy body disorders by injecting alpha-synuclein fibrils directly into olfactory structures in mice. As expected, smell loss was elicited and Lewy pathology was transmitted deep into the brain, followed by cell loss and neurological deficits. To determine if Hsp70 can be delivered into affected tissues to mitigate the pathology of Parkinson?s disease, we also collected pilot data showing that: (1) Hsp70 gains rapid access into the deep recesses of the mouse brain following intranasal infusions, (2) intranasal infusions of Hsp70 mitigate olfactory deficits and alpha-synucleinopathy in preliminary studies on old mice, (3) inhibition of Hsp70 dramatically exacerbates Lewy pathology and neurodegeneration in primary neuron models, and (4) male mice exhibit more smell impairments, Lewy-like pathology, and cell loss than females, consistent with a higher risk of Parkinson?s disease in men.
In Aim 1, we will investigate the kinetics of Hsp70 entry from the nose into the brain, including to the medulla oblongata of the brainstem and substantia nigra of the mesencephalon.
In Aim 2, we will inject mice with alpha-synuclein fibrils and then deliver Hsp70 into the nose beginning 4.5 months later, when motor and olfactory symptoms have already emerged, according to pilot studies. Animals will then be infused with Hsp70 daily for 9 months, until 13.5 months post-fibril injection. Olfactory, motor, and cognitive deficits will be examined monthly. Lewy-like inclusions and neuronal cell bodies will be counted in a number of brain regions, including the substantia nigra, to determine if progressive spread of Lewy pathology into additional regions over time is mitigated even when the therapy commences after pathology has taken root. If these findings translate to humans, non-invasive Hsp70 infusions might radically transform the treatment of Parkinson?s disease and a number of other conditions. Hsp70 falls into the ?biologics? class of drugs, which are currently at the forefront of therapy development and have revolutionized the treatment of many disorders. Unlike current treatments that only mask clinical symptoms, extracellular Hsp70 may decelerate the cell-to-cell spread of misfolded proteins and mitigate the proteotoxicity underlying Lewy body disorders. Thus, the potential impact of our studies on the economic and social cost of these diseases is considerable.
Lewy pathology in Parkinson?s disease and dementia with Lewy bodies may travel through neuroanatomical circuitry from olfactory structures deep into the brain. Here we intend to slow this transmission of pathology from olfactory induction sites by leveraging the chaperone properties of heat shock protein 70. We hope to develop a translatable, non-invasive regimen that delivers heat shock protein 70 into the brain after inhalation through the nose.
| Leak, Rehana K; Calabrese, Edward J; Kozumbo, Walter J et al. (2018) Enhancing and Extending Biological Performance and Resilience. Dose Response 16:1559325818784501 |
