Treatment of synucleinopathies
This invention relates generally to treating synucleinopathies in subjects that are not clinically diagnosed with a lysosomal storage disease, as well as associated methods of making medicaments and screening methods.
1. A method of treating a subject with a synucleinopathy, but not a clinically diagnosed lysosomal storage disease, the method comprising administering to a subject any one or more of:
a cathepsin D polypeptide,
a procathepsin D polypeptide, and
a polynucleotide encoding a cathepsin D or procathepsin D polypeptide,
in an amount effective to reduce a level of α-synuclein in the subject's nervous system or in the subject's lysosomal compartment.
2. The method of claim 1 , wherein the synucleinopathy is a primary synucleinopathy.
3. The method of claim 2 , wherein the synucleinopathy comprises any one or more of: Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with α-synuclein deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age.
4. The method of claim 1 , wherein the synucleinopathy is a secondary synucleinopathy.
5. The method of claim 4 , wherein the synucleinopathy comprises any one or more of: Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia; tau gene and progranulin gene-linked dementia with or without parkinsonism; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease; parkinsonism resulting from neurotoxin exposure; drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); and idiopathic rapid eye movement sleep behavior disorder.
6. The method of claim 1 , further comprising administering one or more agents that enhance autophagy of α-synuclein complexes or enhance degradation of α-synuclein complexes within lysosomes.
7. The method of claim 6 , wherein the agent comprises an mTOR inhibitor.
8. The method of claim 6 , wherein the agent comprises rapamycin or a rapamycin analog.
9. The method of claim 6 , wherein the agent comprises one or more of everolimus, cyclosporine, FK506, hsc70, N-octyl-4-epi-β-valienamine, and glycerol.
10. The method of claim 6 , wherein the agent comprises a small molecule, a large molecule, a peptide, an antibody, a nucleic acid, or a biologically active fragment thereof.
11. The method of claim 1 , wherein the subject's nervous system comprises the subject's central or peripheral nervous system, or both.