Molecular Pathology of Rare Diseases

Prion Lab:

• Understanding the propagation of PrPSc prions.  PrPSc is the first prion to be identified and is the quintessential prion. It causes fatal neurodegenerative ailments such as Creutzfeldt-Jakob disease of humans, scrapie of sheep, bovine spongiphorm encephalopathy (mad cow disease) or chronic wasting disease (zombie deer disease) of cervids. PrPSc is a misfolded conformer of a brain protein termed PrPC.  We aim at understanding how PrPSc propagates. In 2016 we published, in collaboration with colleagues, the first cryoelectron microscopy (cryoEM) study of PrPSc ever. And in 2018, in collaboration with Italian colleagues, the first atomic-level modelization of PrPSc propagation. PrPSc is an amyloid, and PrPC has a C-terminal globular domain featuring and an intrinsically disordered N-terminal domain. We believe that conversion is initiated by attachment of the disordered N-terminal domain to the surface of the PrPSc amyloid. The NH- and CO- groups of the β-strands that make up such surface, are avid to trap and template an incoming disordered PrP stretch. Then, the globular C-terminal domain of that incoming PrPC conformer must unfold partially so it can be templated/refolded from coil to β-strand secondary structure. We are using protein NMR, cryoEM and biochemical techniques to refine our 2018 conversion model.

• Identifying a therapy for prion diseases. Prion diseases are fatal and all attempts to identify a therapy have failed to date. Among these, some of our own. However, these failures have not deterred the many groups that continue to pursue such objective, including ourselves. The recent modest, proof of principle success of the monoclonal antibody Lecanemab for the treatment of AD is an inspiration to persevere.  Currently we are conducting a study based on the use of a fungal prion that is non-infectious to mammals as a vaccine. Our rationale is that the linear amino acid repeats along every amyloid might act as generic antigens.

  We are also participating in an experiment that will be carried out at the International Space Station (launch May 6, 2023) in which we aim at characterizing the interaction of a PrPC folding intermediate and a potential drug targeting it that has been identified in silice. This is a proof of concept experiment and we aim at further pursuing this line of space research.

• Targeting of early amyloid seeds at the initial stage of neurodegenerative diseases. In AD, the amyloid cascade hypothesis posits that the pathogenesis is initially caused by the cerebral deposition of Aβ while in Parkinson’s disease (PD), the pathological aggregation of alpha-synuclein (α-syn) as Lewy bodies in neurons is the key pathological event. Both Aβ and α-syn deposition follow a prion-like mechanism, in which pathogenic amyloid aggregates (seeds), formed early in the aggregation pathway, induce the misfolding and aggregation of proteins in the brain.

  Our hypothesis is that early seeds are different in structure and/or composition than other aggregated amyloid forms (such as fibrils or protofibrils). These unique features make them the ideal target for potential therapeutic agents targeting the initial stage of AD and PD and a promising early biomarker for these diseases.

  We aim to isolate and purify early seeds, biochemically and structurally characterize them, and find therapeutic compounds capable to block their seeding capacity. In parallel, we pursue the development of antibodies against such early seeds with both therapeutic and detection potential.
   

Lipodystrophy Unit (UETeM):

• Murine model of Celia's encephalopathy
• Murine model of type 2 Congenital Genealized Lipodystrophy
• Biometry, BigData and Artificial Inteligence for clinical diagnose of rare lipodystrophy syndromes
• Changes of epigenetic marks in adipose tissue in the pathogenesis of lipodystrophy syndromes
• Pathogenic mechanisms of acanthosis nigricans in severe insulin resistance syndromes
• European registry of lipodystrophies
• Molecular mechanisms of lipomatosis in laminopathic and mitochondrial disorders
• New drugs for treating lipodystrophy co-morbidities