Lysosomal dysfunction as a common mechanism of neurodegenerative diseases

Lysosomal dysfunction as a common mechanism of neurodegenerative diseases
Project start date
15/10/2013
Project end date
14/10/2015
Status
Finished
Project category
Projekti Fonda "jedinstvo uz pomoć znanja"
Grant awarded
1.755.952,96 HRK

Lysosomes are specific cellular organelles that are normally involved in degradation processes of proteins and other damaged organelles. Dysfunction of lysosomes may lead to abnormal protein accumulation which may cause cell degeneration and death. Such protein accumulation also occurs in the brain cells and triggers development of the devastating neurodegenerative diseases in humans, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Although AD and PD are the most common neurodegenerative diseases, there are still no adequate therapies that would prevent or cure AD and PD. In addition, the underlying cellular processes which lead to AD and PD are still not completely understood. In this project we will employ our knowledge and use modern and sophisticated technologies to unravel a molecular mechanism that leads to AD and PD in order to develop targeted and effective future therapies. Recent studies suggest that dysregulation of lysosomes may result in protein accumulation and neurodegeneration. Additionally, it is intriguing that several human rare inherited disorders caused by dysfunction of the lysosomal proteins, such as Niemann-Pick type C disease (NPC), show neurodegeneration and accumulation of proteins characteristic for AD and PD.

Although these findings provide a further evidence for the link between lysosomal dysfunction, protein accumulation and neurodegenerative processes, molecular details of this relationship are largely unknown.Using a lysosomal disorder NPC as a model, the goal of this project is to investigate a role of lysosomal impairment on accumulation of amyloid-beta peptide (Abeta) and alpha-synuclein (a-syn), the two characteristic features in the pathogenesis of AD and PD.We will employ pharmacological treatments and genetic approaches to analyze whether enhancement or inhibition of the lysosomal function can rescue accumulation of Abeta/a-syn and whether their lysosomal clearance may attenuate neurotoxicity and neuronal degeneration.

In addition, we will use state-of-the-art induced pluripotent stem cell technology to generate human NPC neurons by reprogramming the NPC patients’ fibroblasts. The human NPC neurons will be used to validate the relevant targets that are involved in lysosomal function, accumulation of Abeta/a-syn and neurodegeneration. This project will generate new ideas for an effective and highly specific therapy against neurodegenerative diseases, including AD and PD. Our results may provide evidence that lysosomal dysfunction is a common mechanism that leads to neurodegeneration and may lead to development of a novel therapeutic strategy against neurodegenerative disorders.

Project leader / principal investigator

Silva Katušić Hećimović, Doc, Ph.D.

Senior Research Associate +385 1 457 1327
Silva Katušić Hećimović

Associates
logo1
krainc
  Dimitri Krainc, MD

  Chair, Department of Neurology
  Director, Center for Rare Neurological Diseases (CRND)
  e-mail: krainc@northwestern.edu
  Homepage

unknown
  Jessica McDonald, PhD

  e-mail: jessica.mcdonald@northwestern.edu

logo2

Martina Malnar, PhD

senior assistant +385 1 457 1284
Martina Malnar
Mirsada Čaušević - You do not have permission to view this object.
Stjepko Čermak - You do not have permission to view this object.
Notes

 

Results

The overall goal of this project was to unravel the molecular mechanism(s) of protein accumulation in the brain leading to neurodegenerative disorders, among which Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common. In particular, we were interested to analyze how dysfunction of lysosomes, the primary cellular catabolic compartments involved in degradation of proteins and other damaged organelles, may contribute to neurodegenerative processes and whether upregulation of lysosomal function may be used as a novel treatment strategy against these devastating diseases. To test this we used a childhood neurodegenerative disorder Niemann-Pick type C (NPC) as a model that has previously shown to share number of similarities with AD. The NPC disease is a rare inherited lysososomal cholesterol storage disorder caused by mutations in NPC1/NPC2 genes.

  1. Our results revealed that cholesterol accumulation in NPC disease causes a partial dysfunction of lysosomes and that accumulation of amyloid-beta peptide (Abeta), which accumulates in AD brains, may partly be due to its decreased degradation via lysosomal organelles.
  2. In contrast to Alzheimer’s Abeta, we did not observe accumulation of Parkinson’s a-synuclein (a-syn) in NPC cells, indicating that there is likely no a common mechanism/pathway of protein aggregation in neurodegenerative diseases and that substrate specificity in regard to its function and/or cellular/brain localization is likely involved in this process.
  3. We showed that cholesterol depletion, even under conditions of NPC1 loss of function, was able to rescue both the lysosomal impairment and Abeta accumulation in NPC cells. Interestingly, we could not reverse NPC disease related lysosomal dysfunction by autophagy/lysosomal upregulation, which has recently been proposed as a promising alternative for clearing aggregated proteins.
  4. We observed that accumulation of the C-terminal fragments (CTFs) of APP, that accumulate in NPC disease brains along with Abeta peptides, could also add to neurotoxicity and neuronal loss.
  5. We were able to mimic AD-like pathological features in human NPC disease neurons that we derived from NPC patients fibroblasts using induced pluripotent stem cell technology. Indeed, the human NPC patient’s neurons showed a characteristic accumulation of intracellular Abeta and of hyperphosphorylated tau protein, indicating that human NPC neurons can be used as a valuablein vitromodel for drug discovery. 
DMM Latest Articles