Welcome to the AD/PD™ 2021 Interactive Program
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- Live Session | 
- On Demand Session | 
- On Demand with Live Q&A
The viewing of sessions, cannot be accessed from this conference calendar. All sessions are accessible via the Main Lobby.
FOLLOWING THE LIVE DISCUSSION, THE RECORDING WILL BE AVAILABLE IN THE ON-DEMAND SECTION OF THE AUDITORIUM.
MITOCHONDRIAL DYSFUNCTION IS A HALLMARK OF THE EARLY PHASE OF SPORADIC PARKINSON’S DISEASE
Abstract
Aims
Capturing the molecular processes that occur in the earliest stages of sporadic Parkinson’s disease (PD) is key to understanding the pathogenesis of disease. Early Braak stage PD brain exhibits a restricted distribution of pathology, and notably the pathological hallmark of neuronal inclusions, exist in a gradient from unaffected-mild-moderate-severe. This spatial pathological gradient provides an opportunity to capture the earliest biochemical changes occurring in the PD brain.
Methods
We combined unbiased large-scale profiling of protein expression using mass spectrometry across 9 Braak brain regions along this gradient (unaffected-severe) to discover common pathways that reflect key processes in early sporadic PD.
Results
Results demonstrate that mitochondrial dysfunction is common to affected PD brain regions. Moreover, alterations in mitochondrial protein expression occur prior to the appearance of significant α-synuclein pathology. Mitochondrial enzyme activity assays support the existence of a gradient of mitochondrial function in PD brain, with a reduction in multiple mitochondrial complexes evident in the severely affected regions, and only a complex 1 deficiency in mildly affected regions.
Conclusions
This study places mitochondrial dysfunction, with α-synuclein aggregation, at the early stages of pathology in the PD brain, rather than as an end stage bystander effect. We further identified key proteins that are altered in regions unaffected by alpha-synuclein pathology, indicating that these markers precede protein aggregation and neuronal death. Our study suggests that mitochondrial function underlies both the cell vulnerability and pathogenic processes in all pathological stages of early PD brain, and is a hallmark of early disease.
SYSTEMS MODELLING OF MITOCHONDRIAL BIOENERGETICS TO EXPLORE MOLECULAR DEFECTS CONTRIBUTING TO PATHOGENESIS IN PARKINSON’S AND OTHER NEURODEGENERATIVE DISEASES
Abstract
Aims
Mitochondrial bioenergetic dysfunction is known to play a key role in Parkinson’s pathogenesis and other neurodegenerative diseases. Here, we combined a systems model of mitochondrial bioenergetics with biochemical studies to pinpoint and explore bioenergetic molecular dysfunction in Parkinson’s.
Methods
We first performed sensitivity analysis and unsupervised clustering to computationally predict the impact of mitochondrial respiratory chain defects on key bioenergetic parameters. We next integrated experimental data from several transgenic animal models to identify putative molecular defects explaining their bioenergetic phenotype.
Results
Our previous computational analysis identified pre-symptomatic glycolytic dysregulation in an animal model of Alzheimer’s (Theurey et al., 2019). Our sensitivity analysis now provides an in-depth resource detailing the holistic effects of neurodegeneration-associated mitochondrial bioenergetic defects on key bioenergetic parameters. We verified that the bioenergetic defects observed in Parkin knockout brain tissue (Giguere et al., 2018) can be explained by partial mitochondrial uncoupling. Interestingly, only a combined defect in complex I and cytosolic ATP consumption/proton leak could explain the bioenergetic phenotype measured in neurons from PINK1 knockout mice. As part of the PD-MitoQUANT project (www.pdmitoquant.eu), functional and ‘omics data from α-synuclein toxicity models will be incorporated to elucidate the effect of α-synuclein toxicity on mitochondrial bioenergetics.
Conclusions
In summary, we here interrogated a systems model tool to explore putative bioenergetic molecular defects contributing to Parkinson’s pathology and other neurodegenerative diseases. These techniques are now being applied to investigate the effect of α-synuclein toxicity on mitochondrial bioenergetics.
DRP1 AND TAU INCREASE MITOCHONDRIAL FISSION IN AMYOTROPHIC LATERAL SCLEROSIS
Abstract
Aims
Although mitochondrial dysfunction has been widely described in amyotrophic lateral sclerosis (ALS), the mechanisms underlying these alterations remain to be elucidated. Here, we sought to verify whether the accumulation of the microtubule binding protein tau, and dynamin-related protein 1 (DRP1), the GTPase catalyzing mitochondrial fission, cause mitochondrial fragmentation in ALS.
Methods
Synaptoneurosomes (SNs) were prepared from ALS and control post-mortem motor cortex (mCTX). Western blots, and immunohistochemistry were used to assess tau, and DRP1 levels. Mitochondrial number and axonal degeneration were assessed by electron microscopy. DRP1 and tau interactions were studied by co-immunoprecipitation (co-IP). Mitochondrial morphology was assessed in SH-SY5Y cells following treatment with tau, ALS or control SNs in the absence or presence of DRP1 silencing (siDRP1) and a selective tau degrader (QC-01-175).
Results
Our results indicate that there was a decrease in the number of mitochondria in ALS together with an increase in DRP1. Furthermore, tau fibrils were observed in the white matter from ALS mCTX together with an increase in axonal degeneration. Additionally, hyperphosphorylated tau mis-localized to the synapses, and was shown to interact with DRP1 in ALS. Lastly, treatment of SHSY5Y cells with ALS SNs, enriched in both pTau and DRP1, significantly increased mitochondrial fission by reducing mitochondrial length and volume. Importantly, knocking down DRP1 or reducing tau levels significantly mitigated alterations in mitochondrial length and volume induced by ALS SNs.
Conclusions
Together, our findings suggest that increases in DRP1 and pTau cause mitochondrial fragmentation in ALS and importantly targeting this molecular pathway mitigates these alterations.
ALTERATIONS IN WWOX LEVELS LEAD TO MITOCHONDRIAL DYSFUNCTION IN AMYOTROPHIC LATERAL SCLEROSIS.
Abstract
Aims
Understanding the pathogenic mechanisms leading to amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Here, we sought to determine whether alterations in the WW domain-containing oxidoreductase (WWOX), a protein involved in DNA damage response, oxidative stress, and neurodegeneration, may contribute to ALS pathogenesis.
Methods
Genetic data from ALS patients were obtained from Project MinE data browser. Western blots were used to assess alterations in WWOX levels as well as in the levels of proteins involved in the mitochondrial electron transport chain (mtETC) in ALS and control post-mortem motor cortex (mCTX). Interactions between WWOX and mtETC proteins were assessed by co-immunoprecipitation (co-IP). SH-SY5Y cells were used to assess cell viability, mtETC proteins levels, and mitochondrial morphology following treatment with wild-type and mutant recombinant WWOX proteins (rWWOXWT, rWWOXSTOP261E and rWWOOXSTOP353Q).
Results
WWOX levels were decreased in ALS mCTX. Furthermore, there were rare, genetic variants in WWOX in 4,366 ALS samples from Project MinE. Two mutations (WWOXSTOP261E and WWOXSTOP353Q) were identified in the short-chain alcohol dehydrogenases (SDR) domain involved in regulating the mtETC. Furthermore, our data demonstrated a significant decrease in ATP5A and COXII levels in ALS mCTX and revealed that WWOX interact with ATP5A. To link mutations in WWOX to mitochondrial dysfunction, SH-SY5Y cells were treated with rWWOXSTOP261E and rWWOXSTOP353Q. Both rWWOXSTOP261E and rWWOXSTOP353Q induced mitochondrial dysfunctions and decreased mtETC proteins levels. Lastly, rWWOXSTOP353Q reduced mitochondrial length in treated SH cells.
Conclusions
Together, our results suggest that mutations in WWOX may contribute to mitochondrial dysfunction in ALS.
OXIDATIVE STRESS LINKS BRAIN INSULIN RESISTANCE AND MITOCHONDRIAL DEFECTS IN DOWN SYNDROME BRAIN EARLY IN LIFE: IMPLICATION FOR NEURODEGENERATION
Abstract
Aims
Dysregulation of brain insulin signaling and mitochondrial activity with reduced downstream neuronal survival and plasticity mechanisms are fundamental abnormalities observed in Alzheimer's disease (AD). This phenomenon, known as brain insulin resistance (BIR), is associated with poor cognitive performance, and is driven by the inhibition of IRS1 protein. Since Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration in DS and whether they contribute to early onset AD in DS.
Methods
We evaluated levels and activation of proteins involved in the insulin signaling pathway (IR, IRS1, BVR-A, MAPK, PTEN, Akt, GSK3β, PKCζ, AS160, GLUT4) in the frontal cortex of Ts65dn mice (DS model) and euploid (n=6/group) at different ages (1, 3, 9 and 18 months). Furthermore, we analyzed whether changes of brain insulin signaling were associated with alterations of: (i) proteins regulating brain energy metabolism (mitochondrial complexes, hexokinase-II, Sirt1); (ii) oxidative stress (OS) (HNE, 3-NT); (iii) APP cleavage; and (iv) proteins mediating synaptic plasticity mechanisms (PSD95, syntaxin and BDNF).
Results
Ts65dn showed an overall impairment of the above-mentioned pathways, which starts at 1 month, during brain maturation and persists through old age. The accumulation of inhibited IRS1, together with the uncoupling among the proteins downstream from IRS1, characterize Ts65dn mice. Furthermore, reduced levels of mitochondrial complexes and Sirt1, as well as increased OS also were observed.
Conclusions
We propose a close link among BIR, mitochondrial defects and OS that drives the impairment of energy metabolism early in life in DS, thus contributing to early onset AD.