Research Team

Research Outlook

Amyloids in Neurodegeneration | Misfolding in mitochondrial diseases | Funding

Mobirise

Our research at ULisboa aims to decipher molecular mechanisms underlying protein folding diseases.

We study protein aggregation mechanisms and its regulation by molecular chaperones in neurodegenerative diseases including  Alzheimer's Disease 

We also investigate loss of function due to protein misfolding in several mitochondrial metabolic and neurological diseases.

Mobirise

We combine molecular, cellular and biochemical experimental approaches to investigate protein structure and self-assembly in vitro and in cells.

Implemented techniques comprise:
● Purification of disease causing proteins (Aβ, Tau, Syn)
● Mechanistic analysis of amyloid aggregation kinetics;
● Structural biophysics analysis (CD, ATR-FTIR fluorescence)
● Enzymatic assays (ETC, β-oxidation)
● cell toxicity and RT-QuIC assays.

Mobirise

The laboratory is a vibrant workplace composed by passionate and curious team members from different backgrounds, nationalities and training levels.

Team effort is driven by high-quality, thorough research in protein biochemistry and biophysics.

We regularly welcome visiting professors in sabbatical periods and international students in short term research internships.

Mobirise

Through collaboration we summon knowledge, methodological resources and training opportunities for team members that allow tackling our research questions in a multidisciplinary perspective, from molecules, to cells to organisms.

Our collaborative network includes +10 research institutions worldwide and includes physicists, computational biologists, mathematicians, cell biologists and clinicians.

Protein aggregation and amyloids in neurodegeneration

Mechanisms of
amyloid formation

Understanding the mechanistic aspects of protein self-assembly and amyloid formation  is critical to establish cellular and molecular modulators of protein aggregation in the diseased brain.

Through kinetics and mechanistic analysis, we are investigating amyloid formation by Aβ, Tau and Syn.

We seek to establish how cellular conditions, small molecules and antibodies influence protein aggregation, to assist in defining better therapies.

 Cristóvão et al (2018) Sci. Adv.
 Moreira et al (2019) IJMS

S100 proteins in Alzheimer’s Disease 


S100 proteins are recognized biomarkers for brain distress in neurodegenerative conditions including Alzheimer’s.

We seek to uncover novel molecular mechanisms implicating S100 proteins, that link aggregation and neuroinflammation cascades.

For instance, we are combining in vitro assays and studies in animal models to analyse expression levels of S100 proteins in correlation with their spatial distribution within neuronal protein inclusions.


Inhibitors of
amyloid formation

We recently uncovered novel neuro-protective functions which imply S100 alarmins in vital house-keeping processes that harness AD.

Specifically, we found that under physiological conditions mimicking early disease states, S100B acts as a new type of molecular chaperone delaying aggregation.

This is achieved through binding of monomeric Aβ to S100B.



Ongoing research is further dissecting the function of these chaperones, combining spectroscopic, molecular, and kinetic approaches

Brain metal ions and protein aggregation 



In neurodegeneration, imbalance in metal ion homeostasis results in altered homeostasis with deleterious consequences.

On the one hand, we are investigating how metal-protein interactions influence protein aggregation and the oligomers landscape.

On the other hand, we focus on metal binding proteins that can act as scavengers regulating amyloid aggregation and toxicity.

 Moreira et al (2019) IJMS
 Hagmeyer (2018) Front Mol Neurosci
 Leal et al (2012) Coord. Chem. Rev.

Protein misfolding in mitochondrial diseases



Bárbara J. Henriques, PhD
Coordinates projects in protein misfolding in rare mitochondrial diseases.


Inborn errors of metabolism comprise a class of rare genetic diseases many of which are associated to mutations that cause protein folding defects due to early degradation or loss of function.

However clear genotype-phenotype relationships accounting for effects of misfolding are missing.

So far, our research has focused on mitochondrial β-oxidation disorders such as Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) and Glutaric Aciduria type I (GA-I), which are caused by mutations in redox flavoenzymes. 

A new line of research is now focusing on neurological diseases caused by defects in mitochondrial aminoacyl-tRNA synthetases.

Major previous contributions from our lab on this field:

Uncovering structural basis for disease causing mutations
 BBA 2020
 Curr Mol Med. 2019
 Free Radic Biol Med. 2012 

Definition of the molecular rational for the riboflavin-based therapies
 J. Biol. Chem 2009
 Curr Drug Targets 2016

Proof of concept for suitabilty of the fruitfly as potential model for MADD BBA Mol Basis Dis 2012

Misfolding and metabolite induced effects on disease protein variants


We are interested in understanding effects of clinical mutations in β-oxidation flavoenzymes. 

Current work involves
● analysis of structural and functional effects of mutations;
● Functional analysis of mitochondrial bioenergetics;
● study of non-enzymatic post-translational modifications caused by accumulation of specific metabolites under disease conditions. 

Specifically, we are investigating how succinylation and glutarylation influence protein structure and function, and we are using patient-derived cells to carry out functional assays in isolated mitochondria.


Protein dysfuntion in aminoacyl-tRNA synthetase-related neurological diseases 


Around half of mitochondrial diseases are caused by defects in mitochondrial protein synthesis, which have been associated with mutations in aminoacyl-tRNA synthetases (aaRS).

Mutations in aaRS account for neurological disorders and +150 mutations have been reported.

However, mitochondrial aaRSs are relatively poorly characterized and the mechanisms underlying protein dysfunction are not fully established.

We are combining in vitro biochemistry and structural biophysics studies on purified proteins with ex vivo studies on patient-derived fibroblasts, in collaboration with Professor Rita Horvath at Cambridge University (UK).

Protein Misfolding and Amyloids in Biomedicine | Faculdade Ciências Universidade de Lisboa
Department Chemistry and Biochemistry | Biosystems & Integrative Sciences Institute
FCUL C8 Campo Grande - 1749-016 Lisboa - Portugal | Contacts

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