Nome progetto:
The neuronal role of lipids: from molecular function of genes to identification of biomarker in juvenile spastic paraplegia forms

Principal Investigator: Genny Orso (21/11/1975)

Inizio progetto:01/02/2014 – Fine progetto: 31/01/2017

Budget: 220.000 Euro


  • Andrea Martinuzzi
  • Andrea Daga
  • Mariateresa Bassi
  • Marianna Fantin
  • Erica Zaranella
  • Sentiljana Gumeni


fond-cariparo     IRP


In recent years, increasing evidences proved that lipid metabolism is crucial for neuron maintenance and functionality given that imbalance in lipid regulation is linked to different neurodegenerative diseases. The evaluation of the role of lipid metabolism in early onset cases of Hereditary Spastic Paraplegia (HSP) is the core of this project. Different evidences prompt us to analyze this specific aspect of axon degeneration in HSP pathogenesis in order to define if lipid metabolism is a common pathway where to set diagnostic marker and pharmacological treatment. The direct involvement in lipid regulation of the novel SPG (Spastic Paraplegia) genes identified in the last year as well as the discovery that Lipid Droplets (LDs) biogenesis is modified by SPG genes involved in endoplasmic reticulum shaping, prompted us to investigate this pathway in more detail. Our preliminary data obtained from Drosophila models of SPG genes such as REEP1 and spastin suggested a defective regulation of LDs turnover and triglyceride level. We thus think that a primary or secondary defect in lipid regulation represents an important crossway where the metabolic consequences of the derangement in various gene products converge into causing neurodegeneration. We propose a multidisciplinary approach that brings together methodologies and expertizes that range from in vivo analysis of Drosophila models, to bioinformatics techniques and in vitro cell studies and metabolomic profiles of patients in order to define the role of lipids in axonopathies. To evaluate our hypothesis we propose to better clarify the pathogenetic mechanism of SPG genes by using Drosophila as model system for in vivo analysis, and patient fibroblasts for in vitro studies in order to define phenotypes associated with specific mutations. These data will be correlated with the information that we will obtain from the metabolic profile of plasma and urine from HPS patients. Finally, compounds active on lipid metabolism will be applied to our cell and drosophila models to modulate and possibly ameliorate the neuronal and cell phenotypes. The large amount of information gathered at the cellular level, the animal phenotyping and the serum/urine level is expected to expand our knowledge of the metabolic changes produced by mutations in SPG genes, and will lead to the identification of possible biomarkers for an early diagnosis of the disease and to the detection of biochemical/molecular targets for possible therapeutic intervention .