Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia
Introduction
α-Synuclein (α-Syn) is ubiquitously expressed in brain and is highly enriched in presynaptic nerve terminals, where its chief physiological function is the regulation of synaptic levels of monoamine neurotransmitters through modulation of vesicular release (Murphy et al., 2000) and their cognate transporters (Wersinger and Sidhu, 2005, Wersinger et al., 2006a, Wersinger et al., 2006b). Overexpression of α-Syn, through its gene duplication and triplication, is linked to idiopathic Parkinson's disease (PD), while its A30P and A53T mutants cause the autosomal dominant forms of familial PD (Hofer et al., 2004, Krüger et al., 1998, Polymeropoulos et al., 1997). In pathological states, α-Syn becomes misfolded, aggregates and accumulates in neuronal inclusion bodies, Lewy bodies (LBs), seen in PD and other synucleinopathies (Goedert and Spillantini, 1998, Hofer et al., 2004). Tau, a microtubule binding protein, is most commonly linked to Alzheimer's disease (AD) and other tauopathies, where, after hyperphosphorylation, it accumulates in neurons as neurofibrillary tangles [NFTs] (Joachim et al., 1987).
Despite differences in clinical features, pathological and experimental evidence increasingly indicates that there is considerable overlap between tauopathies and synucleinopathies, reinforcing the notion that these diseases may be mechanistically linked. Thus, in AD, 50–60% of patients with NFTs have α-Syn-containing LBs (Lippa et al., 1998, Iseki et al., 1999, Arai et al., 2001, Szpak et al., 2001, Burns et al., 2005, Griffin et al., 2006) and in AD patients with clinically detected extrapyramidal signs, 50% of the patients showed extensive α-Syn pathology colocalized in the substantia nigra with p-Tau (Mori et al., 2002). In PD and in dementia with LBs, costaining of p-Tau has been observed (Duda et al., 2002, Yamaguchi et al., 2005) in 30–40% of the LBs in the nucleus basalis of Meynert and locus coerulus and in 10–30% of LBs in the medulla (Yamaguchi et al., 2005). Extensive overlap in α-Syn and p-Tau pathology has been noted in patients with the A53T mutation (Yamazaki et al., 2000, Kotzbauer et al., 2004), in the Parkinsonism–Dementia complex of Guam (Forman et al., 2002), in dementia with LBs (Yancopoulou et al., 2005), and in familial frontotemporal dementia and progressive aphasia (Hishikawa et al., 2003).
Despite this wealth of pathological information, the molecular and cellular interplay between α-Syn and p-Tau leading to their pathological codeposition is not understood. Under normal physiological conditions, α-Syn is highly soluble. Under pathological conditions, which include oxidative stress and overexpression, the protein becomes insoluble, self-aggregates, and accumulates into LBs (Nemes et al., 2004, Lippa et al., 1998, Iseki et al., 1999, Mori et al., 2002). Similar to α-Syn, Tau is a highly soluble protein that becomes insoluble by pathological hyperphosphorylation at specific sites with ensuing conformational changes and accumulation of the protein into NFTs. Molecular evidence suggests a direct interaction between these proteins, and when incubated together in vitro, α-Syn serves as a seed to accelerate the aggregation of Tau (Kotzbauer et al.,2004).
Using the MPTP mouse neurotoxin model of PD, as well as MPP+ cellular models of PD, we recently demonstrated that increases in α-Syn can initiate and sustain Tau hyperphosphorylation both in vivo and in vitro, with coprecipitation of these proteins (Duka et al., 2006, Duka and Sidhu, 2006, Kozikowski et al., 2006, Duka et al., 2009). The hyperphosphorylation of Tau was absolutely dependent on the presence of α-Syn, as indicated by lack of any p-Tau formation in MPTP-treated α-Syn−/− mice or in neuronal cells lacking α-Syn (Duka et al., 2006, Duka et al., 2009). Moreover, we found that upon oxidative stress by MPTP or MPP+, α-Syn induced p-Tau formation through specific activation and recruitment of p-GSK-3β, activated by autophosphorylation at Tyr216 (Kozikowski et al., 2006, Duka et al., 2009). GSK-3β is a proline-directed serine/threonine kinase, ubiquitously expressed in mammalian tissues, and epitopes phosphorylated by GSK-3β are among the pathological phosphorylation sites of Tau seen in NFTs and paired helical filaments (PHFs) of Alzheimer's disease, and GSK-3β is a major kinase implicated in Tau hyperphosphorylation (Baum et al., 1995).
To examine the clinical relevance of our previous findings, the current studies were undertaken, and these are the first neurochemical examination of the α-Syn/p-Tau/GSK-3β pathway in human postmortem striata and IFG from PD and PD with dementia (PDD). The results show higher neurodegeneration in PDD compared to PD, with tauopathy restricted to striata of both diseases, along with decreased proteasomal activity in the IFG of PDD. Our studies show that unlike Alzheimer's disease where tauopathy is a more global event, tauopathy in brains of PD and PDD has a restricted expression and is limited to dopaminergic neurons of the nigrostriatal region, possibly due to increased dopamine-linked oxidative stress of the latter region.
Section snippets
Materials
The antibodies used in this study are as follows: anti-DAT, MAB369 and TAU MAB361 both from Millipore (Temecula, CA); anti-α-Syn catalog no. 610787, anti-GSK-3β catalog no. 612313, and anti-pGSK-3B – Purified Mouse anti-GSK-3B (pY216) catalog no. 612313, all from BD Transduction Labs (San Jose, CA); anti-parkin ab77924, from Abcam Inc. (Cambridge, MA); and anti-tyrosine hydroxylase sc-25269 and anti-β-actin SC-1616, both from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). The CP-13 and PHF-1
Expression levels of tyrosine hydroxylase and dopamine transporter in human post mortem brains of PD, PDD, and age-matched controls
Since decreases in tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels indicate the extent of loss of monoaminergic neurons and loss of dopaminergic nerve terminals, respectively, we examined expression levels of these proteins in post mortem striata (Fig. 1A) and inferior frontal gyri (IFG; Fig. 1B) from PD, PDD, and controls using Western blots. In striata (Fig. 1A), TH levels were decreased by ~ 40% in PD and PDD cases (p < 0.01). In the IFG (Fig. 1B), TH levels were significantly
Discussion
We show here for the first time an increased state of tauopathy and an increase in associated proteins that modulate this pathway in Parkinson's disease, α-Syn and p-GSK-3β, in postmortem striata of both PD and PDD patients. Our findings demonstrate a large increase in Tau abnormally hyperphosphorylated at Ser202, Ser262, and Ser396/404 in the striatum of PD patients, with a similar increase seen in Ser262 and Ser396/404 in PDD patients; notably, Ser202 levels were not increased in striatum of
Acknowledgments
We are grateful to Peter Davies (Albert Einstein College of Medicine, NY) for the generous gift of the CP-13 and PHF-1 antibodies. We are grateful to Dr. Dianca Graham for work on unpublished studies that enabled us to form some of our conclusions. We are grateful to the families of the many patients for their generosity in donating the organs that made this study possible and to Sun Health Research Institute Brain Donation Program of Sun City, Arizona for the provision of human brain tissue.
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2023, NeuroscienceCitation Excerpt :Tau protein is a pathological marker for certain neurodegenerative diseases, including AD (Spillantini and Goedert 2013). The latest evidence disclosed an association between the tau gene (MAPT) and sporadic PD, suggesting the potential role of tau in PD (Simon-Sanchez et al. 2009; Edwards et al. 2010; Wills et al. 2010). In 2016, Shi and co-workers demonstrated that tau was detectable in blood, and they quantified exosomal tau using a kind of single molecule array kit—Simoa (Shi et al. 2016).