Here I'll point out a recent review of approaches to treat one of the more common synucleinopathies, conditions related to - and thought to be caused by - the abnormal accumulation of α-synuclein in tissues. The pathologies of numerous age-related diseases are linked to various different types of protein aggregate that are observed to build up with age: misfolded or simply overabundant proteins that precipitate to form solid clumps and fibrils. Amyloids are well known for their association with Alzheimer's disease, but there are many types of amyloid and many corresponding amyloidosis conditions. Similarly tau aggregates are linked to the tauopathies. The list goes on, and of course includes α-synuclein.
Why do these various different aggregates appear in old individuals but not young ones? Most of the evidence to support various theories comes out of Alzheimer's research, as that field has far more funding and far more scientists working on the problem. Amyloid levels in the brain are dynamic on a fairly short timescale, and the buildup of amyloid has the look of slowly failing clearance mechanisms. These might include general dysfunction in the choroid plexus filtration of cerebrospinal fluid, or in the drainage channels that carry away metabolic waste from the brain, or the mechanisms of the blood-brain barrier intended to shunt unwanted waste out of the brain and into the blood system. These and related forms of dysfunctions could plausibly arise from many of the forms of cell and tissue damage thought to cause aging, or from their consequences such as inflammation, loss of muscle strength, loss of tissue flexibility, and so forth.
The most promising near term approach to protein aggregates is to build treatments than can be periodically applied to clear out the buildup. Immunotherapies are so far the best of ongoing efforts, enlisting the immune system to attack and break down the aggregates, but there is still a way to go towards robust and reliably outcomes. Clinical trials have so far been disappointing, as is often the case in the first round of attempts in any area of medicine. Equally, other classes of rejuvenation therapy will be needed to repair the problems in clearance of aggregates that cause the buildup in the first place: just getting rid of the aggregrates themselves isn't a full solution, just a much better class of sustaining treatment than is presently available.
Work on clearing α-synuclein runs in parallel to work on amyloid-β, and with the same general pattern of progress, in that immunotherapies look to be the best path forward for now, yet only incremental benefits have been shown to date via this appreach. This review is focused on Lewy body dementia, but the approaches to clearing α-synuclein might be applied to any of the other synucleinopathies, such as Parkinson's disease.
Dementia with Lewy bodies (DLB) is the second most common pathologic diagnosis of dementia, following Alzheimer's disease (AD), comprising 25% of all dementias. The pathologic feature of DLB is the presence of Lewy bodies in the cortex and brainstem. Lewy-bodies are neuronal inclusions of abnormal filamentous assemblies of α-synuclein and ubiquitin. It is very difficult to distinguish DLB from dementia-associated with Parkinson's disease (PD), which shares many underlying clinical and pathological features with DLB. The major component of Lewy bodies in DLB and Parkinson's disease (PD) is misfolded α-synuclein. The normal α-synuclein is a soluble protein and is involved in presynaptic processing of neurotransmitters, mitochondrial function and proteasome processing. In DLB and PD, α-synuclein aggregates in Lewy bodies and causes neuronal death. Therefore, various strategies have been employed to reduce α-synuclein directly for the treatment of DLB and PD.
Secreted, extracellular α-synuclein might play a crucial role in the passage of misfolded α-synuclein from one cell to another. Therefore, immunotherapy targeting extracellular α-synuclein has been proposed, and it was found that immunization with recombinant human α-synuclein led to a reduction in α-synuclein accumulation and neurodegeneration without neuroinflammation. It was also found that administration of anti-α-synuclein antibody into the brains of PGDF-α-synuclein transgenic mice prevented cell-to-cell transmission of α-synuclein. The antibodies aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Misfolded extracellular α-synuclein might interact with antibodies to form antigen-antibody complexes, and these complexes are endocytosed and transferred to the lysosomal compartment for degradation through autophagy.
Recently, AFFiRiS AG, an Austria-based biotech company, developed a vaccine targeting PD and other synucleinopathies. The peptides used in the vaccine are designed to be too small to induce an α-synuclein-specific T cell response, thus avoiding T cell autoimmunity. The vaccine was tested in transgenic mouse models. Active vaccination resulted in decreased accumulation of α-synuclein oligomers in axons and synapses, reduced neurodegeneration, and improvements in motor and memory deficits in both models. Phase I clinical trials are currently ongoing.
Another strategy targeting α-synuclein is RNA interference (RNAi). Direct infusion of siRNA led to the reduction of α-synuclein. Recent studies have employed virally-mediated RNAi delivery, using lentivirus-mediated RNAi to successfully silence human α-synuclein expression in the rat substantia nigra. Other groups have employed AAV-mediated RNAi, but found that this approach caused neurotoxicity. They then tried AAV-mediated RNAi embedded in mircoRNA30 backbone, and they were able to reverse α-synuclein induced forelimb deficit and dopaminergic neuron loss. However, this approach induced inflammation. Transgene delivery using AAV was shown to be safe in previous studies and this technology has been used in human clinical trials in PD.
Other approaches employed to reduce α-synuclein include ribozymes, intracellular expression of single chain antibodies, endogenous microRNA, and mirtrons. A safe and effective approach to reduce the level of α-synuclein will likely slow down or even reverse the progression of DLB.