Curated Optogenetic Publication Database

Abstract: The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer's disease (AD). Increasing evidence implicates nuclear membrane disruption in AD and related tauopathies; however, whether this is a cause or consequence of neurodegeneration remains unresolved. Here, we show that nuclear lamina disruption emerges at the early Braak stages, coinciding with the initial formation of pathological tau aggregates in post-mortem AD brain tissue. Using the tauopathy mouse model (P301S PS19), we demonstrate that oligomeric tau (oTau) directly binds to the Lamin B Receptor (LBR), inducing nuclear envelope invaginations as revealed by electron microscopy. These structural alterations are accompanied by chromatin remodeling and gene expression dysregulation. To dissect the underlying mechanism, we employed a light-inducible OptoTau system (4R1N Tau::mCherry::Cry2Olig) in human iPSC-derived neurons, enabling real-time visualization of tau aggregation dynamics. This system revealed selective recruitment of oTau to the nuclear envelope and direct interactions with LBR and Lamin B2, leading to nuclear deformation and activation of the protein translational stress response. Together, these findings identify nuclear membrane disruption as an early and potentially causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization, nuclear stress, and chromatin remodeling. Targeting nuclear destabilization may offer new therapeutic avenues for mitigating AD pathogenesis.

Abstract: The aggregation of α-synuclein (α-SYN) into Lewy bodies (LBs) is a central event in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies1,2. Despite significant advances in understanding α-SYN self-assembly, the precise sequence of early aggregation steps has not been directly visualized in living neurons. Here, we use an optogenetic-induced protein aggregation system with a high temporal resolution to monitor the onset of α-SYN assembly in neurons. We found that the initiation and accumulation of α-SYN aggregates occur predominantly at the lysosomal membrane, an event driven by the α-SYN N-terminus and modulated by the membrane-associated adaptor protein WD repeat-containing protein 44 (WDR44). Remarkably, we demonstrate that WDR44 knockdown markedly reduced de novo α-SYN aggregation in both neuronal cultures and in vivo, whereas WDR44 overexpression enhances α-SYN aggregation in PD patient-derived iPSC neurons. Consistent with its potential pathogenic involvement, WDR44 aberrantly accumulates in vivo and in the brains of PD patients, where it colocalizes with LB inclusions. Finally, we show that lysosome-associated α-SYN aggregates compromised lysosomal structure and function, leading to neuronal impairment, a phenotype worsened by WDR44 overexpression, linking early aggregation events to downstream toxicity. Together, these findings reveal the earliest dynamic stages of α-SYN oligomerization in living neurons and identify the WDR44-α-SYN interaction as a promising therapeutic target for reducing α-SYN pathology and enabling early intervention in PD.