Tau missorting and spastin-induced microtubule disruption in neurodegeneration: Alzheimer Disease and Hereditary Spastic Paraplegia

Abstract

In Alzheimer Disease (AD), the mechanistic connection of the two major pathological hallmarks, namely deposition of Amyloid-beta (Aβ) in the form of extracellular plaques, and the pathological changes of the intracellular protein Tau (such as phosphorylation, missorting, aggregation), is not well understood. Genetic evidence from AD and Down Syndrome (Trisomy 21), and animal models thereof, suggests that aberrant production of Aβ is upstream of Tau aggregation, but also points to Tau as a critical effector in the pathological process. Yet, the cascade of events leading from increased levels of Aβ to Tau-dependent toxicity remains a matter of debate.Using primary neurons exposed to oligomeric forms of Aβ, we have found that Tau becomes mislocalized (missorted) into the somatodendritic compartment. Missorting of Tau correlates with loss of microtubules and downstream consequences such as loss of mature spines, loss of synaptic activity, and mislocalization of mitochondria.In this cascade, missorting of Tau induces mislocalization of TTLL6 (Tubulin-Tyrosine-Ligase-Like 6) into the dendrites. TTLL6 induces polyglutamylation of microtubules, which acts as a trigger for spastin mediated severing of dendritic microtubules. Loss of microtubules makes cells unable to maintain transport of mitochondria, which in turn results in synaptic dysfunction and loss of mature spines. These pathological changes are absent in TauKO derived primary neurons. Thus, Tau mediated mislocalization of TTLL6 and spastin activation reveals a pathological gain of function for Tau and spastin in this cellular model system of AD.In contrast, in hereditary spastic paraplegia (HSP) caused by mutations of the gene encoding spastin (spg4 alias SPAST), spastin function in terms of microtubule severing is decreased at least for the gene product of the mutated allele, resulting in overstable microtubules in disease model systems. Whether total spastin severing activity or microtubule stability in human disease is also affected is not yet clear. No human disease has been associated so far with the long-chain polyglutamylation enzyme TTLL6, or the other TTLLs (1,5,11) possibly involved.Here we review the findings supporting a role for Tau, spastin and TTLL6 in AD and other tauopathies, HSP and neurodegeneration, and summarize possible therapeutic approaches for AD and HSP.

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…Notably, the amount of tau needed for in vitro LLPS induced with the neutral molecule PEG likely differs from the tau concentration critical for LLPS in a neuron, because (i) the intraneuronal distribution of tau is highly heterogeneous (usually high in the axon and low in the soma and dendrites), (ii) different isoforms and post‐translational modified and truncated forms of tau coexist, (iii) the pool of free soluble tau released from microtubules is highly dynamic depending on phosphorylation, and (iv) multiple other binding partners of tau have been identified that could deplete tau from the free soluble pool available for LLPS. Recently, it has also been shown that the usual distribution of tau in neurons can be changed upon exposure to A‐beta, which can induce the local transcription of tau in dendrites as well (Zempel & Mandelkow, 2015; Li & Götz, 2017). …”

Glutamylation Regulates Transport, Specializes Function, and Sculpts the Structure of Cilia

“…However, a recent report suggested that pathological loss of dendritic spines and synapse activity may be caused by mislocalization of TTLL6 (and possibly of TTLL1, 5, or 11), leading to abnormal glutamylation patterns and excessive spastin-mediated severing of dendritic MTs [44]. …”

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

“…Two major pathological hallmarks in AD are extracellular amyloid plaques and intraneuronal neurofibrillary tangle (NFT; Zhang et al, 2011). NFTs are comprised of hyperphosphorylated microtubule-associated protein tau (Song et al, 2015; Yamada et al, 2015; Zempel and Mandelkow, 2015). Amyloid plaques are primarily comprised of Aβ which is derived from sequential cleavages of APP by β- and γ-secretases (Zhang et al, 2011; Audrain et al, 2016).…”