Accelerating Discovery

PROTEIN MISFOLDING DISORDERS

ER stress is a hallmark feature of secretory cells and many diseases including cancer, neurodegeneration, and diabetes. Our laboratory is particularly committed to investigate the cause of neurological diseases linked to abnormal protein aggregation, including, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Parkinson’s disease, Alzheimer’s disease and Prion-related disorders. We are also exploring the mechanisms underlying tissue regeneration after injury to the nervous system. We are also exploring the possible function of the UPR in the physiology of the nervous system and recently uncovered a novel role in cognition.

What is the contribution of ER stress to neurodegenerative diseases?

Can we intervene the proteostasis network toward disease intervention??

The most common neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, affect millions of people worldwide, but there is neither preventive nor curative therapy for them. All these pathological conditions are linked to the accumulation of abnormal protein aggregates in the brain. Signs of endoplasmic reticulum (ER) stress are observed in most these diseases in animal models and human post mortem samples studies (Hetz and Mollereau 2014 Nature Rev Neurosci). We are currently developing a systematic approach to underscore the consequences of targeting several components of the UPR in brain diseases. Our studies in Chile have obtained important international recognition and have been funded by the most prestigious Foundations in the world including High Q Foundation, CHDI, ALS Therapy Alliance, ALS Association, Muscular Dystrophy Association, ICGEB, AD Association, The Michel J Fox Foundation for Parkinson Research, National Parkinson´s Disease, North American Spine Society and the US Force.



Targeting the UPR in neurodegenerative diseases, a genetic approach

Amyotrophic lateral sclerosis - One of our major research focuses is ALS. ALS is a progressive adult-onset motoneuron disease characterized by muscle weakness, atrophy, paralysis and premature death. The pathological hallmark of ALS is the selective degeneration of motoneurons in the spinal ventral horn, most brainstem nuclei and cerebral cortex. We have defined the contribution of the key UPR regulator XBP1 to ALS using genetic manipulation by creating a conditional knockout mouse for the UPR transcription factor XBP1 in the nervous system (Hetz et al., 2008 Proc Natl Acad Sci). Despite expectations that XBP1 deficiency in the nervous system would enhance the severity of the disease, mouse models were instead markedly more resistant to developing ALS. This phenotype was associated with enhanced clearance of abnormal protein aggregates by autophagy, a cellular pathway involved in lysosome-mediated degradation of abnormal proteins and damaged organelles. Virtually identical results were obtained in models of Huntington´s disease (Hetz et al., 2009 Genes Dev and Vidal et al., 2012 Hum Mol Gen). We have also manipulated ATF4 levels on a disease context. Ablating ATF4 expression delayed ALS possibly involving reduced apoptosis levels (Matus et al., 2013 PLoS One). In contrasts, ATF4 deficiency did not affect Huntington´s disease. Our results depict a complex scenario where depending the disease context; the UPR has highly specific effect on the progression of the disease. We also uncovered a critical homeostatic crosstalk between these two stress pathways that can provide protection against neurodegeneration.

Using genetic manipulation of the pathway we recently uncovered a pathogenic role of the autophagy regulator Beclin 1 in ALS (Nassif et al., 2014 Autophagy). Furthermore, we have recently develop a method to measure autophagy activity in vivo in the nervous system and provided a solution to a global need in the field (Castillo et al., 2013 Cell Death Dis).

More recently, in collaboration with Dr Robert Brown (UMASS) we have screened for mutations in essential ER chaperones in ALS patients and discovered point mutations on two foldases, ERp57 and PDIA1 (Gonzalez-Perez et al., 2015 Gene). On a multidisciplinary study we have defined the impact of these novel mutations to ALS and uncovered a novel role of the ER proteostasis network on sustaining motor function through fine tuning neuromuscular junctions (Woehlbier et al., 2016 EMBO J). This study identified ER stress perturbation as a possible risk factor to the development of ALS.

Parkinson and Alzheimer disease - We recently investigated the contribution of XBP1 to Parkinson´s disease using preclinical models. In our studies, targeting XBP1 in the brain also protected dopaminergic neurons against neurodegeneration (Valdes et al., 2014 Proc Natl Acad Sci). We are currently defining the impact of the UPR to other important diseases such as Alzheimer´s disease and multiple sclerosis. Based on our studies we have further investigated the role of autophagy in neurodegenerative diseases.

The possible function of the UPR in the physiology of the nervous system has been poorly studied. A polymorphism in the XBP1 promoter has been proposed as a risk factor to develop schizophrenia, bipolar disorders and Alzheimer. On a recent attempt to study to function of XBP1 in higher functions of the nervous system we uncovered an unexpected role in learning and memory processes. This activity of XBP1 was mapped to the control of the growth factor BDNF, an essential factor modulating neuronal plasticity (Martinez et al., 2016 Cell Reports).

The Prion protein and Creutzfeldt-Jakob disease - Prion Disorders are fatal neurodegenerative diseases characterized by the spongiform degeneration of the brain accompanied by the accumulation of a misfolded and protease-resistant form of the prion protein (PrP). The most common PrD in humans is Creutzfeldt-Jakob disease (CJD) and in Chile the incidence of this disease is almost triple compared with the rest of the world. Together with the Dr Cartier in Hospital El Salvador (Santiago, Chile) we have developed important studies to diagnose Chilean CJD patients and generated novel tools for proper diagnosis (Torres et al., 2012 PLos One). We also investigated the molecular basis of Prion-mediated degeneration (Hetz et al., 2008 Proc Natl Acad Sci, Torres et al., 2010 PLoS One). On a recent report we discovered the ER foldase ERp57 is crucial to synthetize PrP, controlling its steady-state levels (Torres et al., 2014 J Biol Chem).

Mechanical Injury to the CNS – Spinal cord injury (SCI) is the major cause of paralysis and often affects individuals in their productive age, having an enormous social and economic impact. Together with our collaborator Dr. Felipe Court (P. Catholic University of Chile) we have developed studies supporting an early activation of the UPR after SCI. Using a model of mechanical injury to the spine we reported a fast upregulation of critical ER stress markers in the injury zone in addition to distal areas. This study was awarded with one of the 4 grants funded by North American Spine Society (EEUU) in the world as one of the most outstanding projects. On a recent study we also defined the contribution of ER stress to peripheral nerve degeneration and identified a novel role of XBP1 in axonal regeneration (Oñate et al., 2016 Scientific Reports).

< Back to Research



Hetz Lab © 2012 | Laboratory of Cellular Stress and Biomedicine | Design NV