Fightaging’s post: A Review of Work on Targeting α-synuclein Aggregates

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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.

Disease-modifying therapeutic directions for Lewy-Body dementias