Endogenous accumulation of alpha-synuclein in microglia-containing organoids
Parkinson’s disease is strongly linked to the abnormal accumulation of a protein called alpha-synuclein in the brain. Under healthy conditions, alpha-synuclein is involved in regulating neurotransmitter release at synapses, which helps nerve cells communicate efficiently.
However, in Parkinson’s disease, alpha-synuclein tends to misfold and aggregate, forming insoluble clumps known as Lewy bodies and Lewy neurites inside neurons. These aggregates are particularly harmful to dopamine-producing neurons in the substantia nigra in the midbrain, a crucial region of the brain for controlling movement.
The presence of these toxic aggregates is thought to disrupt cellular processes, impair mitochondrial function, and trigger inflammation, ultimately leading to neuronal dysfunction and cell death. This loss of dopamine-producing neurons results in the characteristic motor symptoms of Parkinson’s disease, such as tremors, rigidity, and bradykinesia (slowness of movement).
Understanding how alpha-synuclein misfolds and spreads in the brain is a major focus of current research, as it could pave the way for new therapies aimed at preventing or reducing aggregate formation and protecting neurons.
While animal models and cell culture systems have provided valuable insights into Parkinson’s disease, they often fail to reproduce the spontaneous, endogenous accumulation of alpha-synuclein aggregates seen in human disease. In most models, researchers must artificially overexpress mutant or wild-type alpha-synuclein or introduce preformed fibrils to induce aggregation. This overexpression or seeding bypasses the naturally occurring misfolding and accumulation processes that happen over decades in humans. As a result, these models do not fully capture the subtle interplay of genetic susceptibility, aging, environmental factors, and complex cellular pathways that drive endogenous alpha-synuclein pathology in Parkinson’s disease. This limitation makes it challenging to translate findings from models directly to human disease and highlights the need for better systems that more faithfully reflect the natural disease process.
A recent study on microglia-containing human midbrain organoids showed exciting results on the endogenous phosphorylation and accumulation of alpha-synuclein. Remarkably, when researchers incorporated microglia carrying three copies of the PD-linked SNCA gene (3× SNCA) into otherwise healthy midbrain organoids, these assembloids developed endogenous phosphorylated alpha-synuclein pathology (pS129) without any overexpression or external seeding. This work demonstrates for the first time that patient-specific microglial genetics alone can trigger spontaneous alpha-synuclein aggregation within a more naturally aged, human-like neural tissue context, suggesting a promising path toward models that truly mimic the pathological process seen in Parkinson’s disease.