Aberrant accumulation of misfolded protein aggregates is associated with neuroinflammation, neuronal death, and progressive cognitive decline in diverse groups of neurodegenerative diseases (Ross and Poirier, 2004; Sweeney et al., 2017; Soto and Pritzkow, 2018; Lashuel, 2021). Alzheimer’s disease, as well as a subset of other neurodegenerative disorders, together referred to as Tauopathies, are defined by accumulated intracellular aggregates of the Tubulin-associated unit (Tau) protein (Iqbal et al., 2010; Jouanne et al., 2017; Pinzi et al., 2023). Despite substantial clinical interest and decades of research, effective therapeutic interventions for treating Tauopathies are still unavailable (Khanna et al., 2016; Lashuel, 2021).
Tau is predominantly expressed in neurons, where it stabilizes microtubules, thus facilitating intra-axonal transport (Avila et al., 2004; Kent et al., 2020; Robbins et al., 2021). Several mutations in the Tau protein have been identified that contribute to a wide spectrum of Tauopathies, including Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) (Goedert and Jakes, 2005; Wolfe, 2009). These pathogenic mutations enhance the propensity for Tau protein hyperphosphorylation at Ser/Thr residues, leading to the formation of neurofibrillary tangles via self-aggregation (Tzioras et al., 2023). The phosphorylated Tau disengages from the microtubule, potentially altering axonal transport and contributing to synapse loss and/or axon retraction (Guo et al., 2020; Tzioras et al., 2023). Thus, the self-aggregation of Tau and destabilization of microtubules may contribute to the progression of Tau pathogenesis. Such a model is supported by studies in Drosophila and rodent models of Tauopathies. Several of these models of tauopathy show disrupted microtubules, synaptic abnormalities, and abnormal motor behavior (Stubbs et al., 2023). Significantly, pharmacological stabilization of microtubules or reducing Tau levels can revert at least some of the defects observed in these Tauopathy models (Zhang et al., 2005; Brunden et al., 2010). However, alternative approaches to mitigate Tau-induced neurodegeneration are required because the currently available microtubule-targeting drugs are toxic at concentrations required to have an effect in the brain (Yu et al., 2021). One approach, suggested by several studies demonstrating a role for chaperone systems in Tauopathies (Perez et al., 1991; Renkawek et al., 1994; Ostapchenko et al., 2013), is to identify and manipulate specific molecular chaperones that directly or indirectly control Tau aggregation and Tau-induced neurotoxicity in vivo (Blard et al., 2007; Darling et al., 2021).
Molecular chaperones facilitate proper protein folding, prevent protein aggregation, and solubilize or facilitate autophagic or proteasomal elimination of protein aggregates (Warrick et al., 1999; Dou et al., 2003; Buchner, 2019). Consistent with this, enhanced expression of Hsp70 or HSP90 chaperones in mouse neuroblastoma N2A cells reduces pathological Tau levels by promoting the partitioning of Tau onto microtubules (Dou et al., 2003). On the other hand, as chaperones stabilize misfolded protein states, the expression of certain chaperones or cochaperones can sometimes also promote and facilitate the aggregation of Tau (Bhattacharya et al., 2020; Criado-Marrero et al., 2021). For instance, expression of HSP90 cochaperones, FKBP52, or Aha1 in the mouse brain enhances Tau aggregation, neuroinflammation, and cognitive decline in the Tau transgenic mouse model (Shelton et al., 2017; Criado-Marrero et al., 2021). These and other data indicate that: (a) chaperones not only alleviate but also aggravate Tau aggregation, and hence identification and analysis of chaperones that modulate Tau-aggregation and toxicity are required to understand biological and pathogenic mechanisms involved in Tauopathy, and (b) genetic or pharmacological manipulation of specific chaperone activities could be of possible therapeutic value for treating Tau-induced neurodegeneration.
Here, we report that Pfdn5 colocalizes with axonal microtubules and physically associates with stable microtubules. Loss of Pfdn5 resulted in a remarkable reduction in tubulin levels, disrupting microtubules in otherwise wild-type Drosophila, as well as the aggregation of Tau in axons and larval brain of the Drosophila hTauV337M disease model. Moreover, Pfdn5 deletion exacerbates Tau-induced neurotoxicity, and overexpression of Pfdn5 mitigates the age-dependent progression of neurodegeneration and suppresses the learning and long-term memory deficits associated with Tau-induced neurotoxicity. These and other observations described in subsequent sections of this paper suggest that (1) In addition to its role as a cotranslational chaperone for tubulin, Pfdn5 has direct roles in the stability of mature microtubule filaments, and (2) Pfdn5 stabilizes microtubules, prevents neuronal loss, and delays the onset of Tau-induced neurotoxicity. Since the overexpression of Pfdn5 restored the Tau-induced neurological abnormalities to the control levels without causing any detectable changes in synaptic morphology, cognitive impairment, or organismal health, we suggest that Pfdn5 could be a possible therapeutic target for Tauopathies.