A pathological hallmark of Parkinson's disease is the presence of Lewy body-like inclusion bodies (LB-like IBs), aggregates of α-synuclein protein, in neurons. LB-like IBs are thought to drive neurodegeneration by impairing proteostasis. More recently, a second type of α-synuclein aggregate, Syn-aggresomes, has been reported. However, the contribution of Syn-aggresomes to proteostasis, and any interplay with LB-like IBs, is unclear. In this study (Mansuri et al., 2024), Swasti Raychaudhuri and colleagues investigate LB-like IBs and Syn-aggresomes in HEK293T cells and primary neurons seeded with amyloid fibrils to induce aggregate formation. Here, the authors show that there is crosstalk between the two aggregates, whereby Syn-aggresomes titrate the biogenesis of LB-like IBs by facilitating degradation of soluble α-synuclein. LB-like IBs are thought to act as a protein quality control (PQC) mechanism by sequestering α-synuclein, as α-synuclein in LB-like IBs remains degradable and is turned over once fibril seeding is ceased. However, if permitted to overgrow, large LB-like IBs become detrimental due to distortion of microtubules and loss of cytoskeleton-nucleoskeleton tension, and thus lead to injuries to the nuclear lamina. Subsequent deregulation of PQC protein expression results in cells becoming proteostasis sensitive. Thus, these findings highlight how perinuclear LB-like IBs, influenced by Syn-aggresomes, initially act as a PQC mechanism, but can become neurodegenerative.
