Tau knockout exacerbates degeneration of parvalbumin‐positive neurons in substantia nigra pars reticulata in Parkinson's disease‐related α‐synuclein A53T mice

Abstract

α‐Synuclein (α‐syn)‐induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule‐associated protein tau, which is considered second only to α‐syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD‐related proteins in vivo remains unclear. To investigate how the expression of tau affects α‐syn‐induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α‐syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α‐syn‐mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α‐syn aggregates, accelerate the severe and progressive degeneration of parvalbumin‐positive (PV+) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety‐like behavior in aged PD‐related α‐syn A53T mice. The mechanisms may be associated with A53T α‐syn‐mediated specifically successive impairment of N‐methyl‐d‐aspartate receptor subunit 2B (NR2B), postsynaptic density‐95 (PSD‐95) and microtubule‐associated protein 1A (MAP1A) in PV+ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV+ neurons, and that inhibition of the impairment of NR2B/PSD‐95/MAP1A pathway, may be a novel and preferential option to ameliorate α‐syn‐induced neurodegeneration.

Templated α-Synuclein Inclusion Formation Is Independent of Endogenous Tau

“…Antibodies to oligomeric tau reduce memory defects and Lewy-body like pathology in mice overexpressing the A53T mutant form of α-synuclein (Gerson et al, 2018). In contrast, absence of tau did not prevent templated spreading of misfolded α-synuclein, or dopamine neuron loss and associated motor deficits in toxin-induced and transgenic models of human-α-synuclein overexpression (Morris et al, 2011;Gratuze et al, 2019;Jiao et al, 2020;Bassil et al, 2021). The effect of tau reduction in PD models, therefore, differs from AD models and further characterization is necessary.…”

Tau Knockout and α-Synuclein A53T Synergy Modulated Parvalbumin-Positive Neurons Degeneration Staging in Substantia Nigra Pars Reticulata of Parkinson’s Disease-Liked Model

“…As described in our previous study, we continued to use the triple transgenic mice that overexpressed PD-related α -syn A53T missense mutation in the midbrain dopaminergic neurons with different tau gene dosage from high to low, which were named as Pitx3-A53T α -Syn × hTau , Pitx3-A53T α -Syn × Tau + / + , Pitx3-A53T α -Syn × Tau +/– , and Pitx3-A53T α -Syn × Tau –/– mice, respectively ( Jiao et al, 2020 ).…”

“…As described previously ( Jiao et al, 2020 ), the line of pituitary homeobox 3 ( Pitx3 ) promoter-controlled tetracycline transactivator ( tTA ) ( Pitx3-tTA ) mice, the lines of human α-syn A53T inducible transgenic mice ( tetO-A53T ) and human wild-type Tau inducible transgenic mice ( tetO-hTau ), in which the expression of human α-syn A53T and human wild-type Tau were under the transcriptional control of tetracycline operator ( tetO ), and the line of Tau –/– mice were used to generate triple transgenic mice and maintained on C57BL/6J background. The mice were reared under specific-pathogen-free (SPF) conditions, with 12-h light/12-h dark cycles and fed a regular diet ad libitum .…”

“…The genotype of the mice was determined by PCR analysis of genomic DNA extracted from tail biopsy and had been further validated histologically, as described in the previous study ( Jiao et al, 2020 ).…”

“…Recently, Lilascharoen et al (2020) indicated that the frequency of quantal-like inhibitory postsynaptic currents was significantly decreased in SNR neurons, which might indeed contribute to immobility in the 6-hydroxydopamine-lesioned PD mice model, as selective manipulation of the SNR-projecting external globus pallidus PV + neurons alleviated the locomotor deficit. Our previous study found that the Pitx3-A53T α -Syn × Tau –/– triple transgenic mice model of PD showed anxiety-like behavior among 12- to 18-mouth-old, which may be related to the substantial degeneration of PV + neurons in the SNR ( Jiao et al, 2020 ). However, the progress and stage marker of PV + neurons loss are still unclear.…”