Method of diagnosis, prognostic or treatment of neurodegenerative diseases

An in vitro method of diagnosis or prognostic or follow-up of a neurodegenerative disease in a subject, or determining whether a subject is at increased risk of developing said neurodegenerative disease, comprising determining a level and/or an activity of:

• a) at least one gene selected from the group consisting of the nucleotidic sequences set forth by SEQ ID NO:
• 1 and SEQ ID NO:
• 3 and coding for an heparan sulfate glucosamine 3-O-sulfotransferase 2 and 4 respectively, and/or
• b) at least one transcription product of a gene selected from the group consisting of the nucleotidic sequences set forth by SEQ ID NO:
• 1 and SEQ ID NO:
• 3 and coding for an heparin-glucosamine 3-O-sulfotransferase 2 and 4 respectively, and/or
• c) at least one translation product of said genes, said products being set forth respectively by SEQ ID NO:
• 2 and 4, and/or
• d) a fragment or derivative or variant of said gene or said transcription or translation product, and/or
• e) heparan sulfate, in particular 3-O-sulfated heparan sulfate, notably 3-O-sulfated heparan sulfate disaccharide, and/or
• f) abnormal phosphorylation of the Tau protein and/or total Tau protein,
• in a sample of a biological fluid previously obtained from said subject and comparing said level and/or said activity to a respective reference value representing a known disease or health status,
• an increased level and/or activity of at least one of said gene and/or said transcription product and/or said translation product and/or said heparan sulfate, in particular said 3-O-sulfated heparan sulfate and/or said abnormal phosphorylation of the Tau protein and/or total Tau protein in the subject sample being indicative of a neurodegenerative disease or a risk of developing said neurodegenerative disease, advantageously a Tauopathy, in particular Alzheimer's disease, provided that said neurodegenerative disease is different from a prion disease, and provided that when said activity and/or the level determined is the one of:
• heparan sulfate, or
• of abnormal phosphorylation of the Tau protein and/or total Tau protein,
• therefore, the activities and/or levels heparan sulfate and abnormal phosphorylation of the Tau protein and/or total Tau protein are both determined, or
• the activity and/or the level of at least one other element chosen among said gene, said transcription product of said genes, said translation product of said genes, or said fragment or derivative or variant of said gene or said transcription or translation product is also determined.

A kit of diagnosing or prognosticating or following-up of a neurodegenerative disease, advantageously a Tauopathy, in particular Alzheimer's disease, in a subject, or determining the propensity or predisposition of a subject to develop such a disease, provided that said neurodegenerative disease is different from a prion disease,

• consisting of means for detecting in a sample of a biological fluid obtained from said subject, a level and/or an activity of:
• at least one transcription product of a gene selected from the group consisting of the nucleotidic sequences set forth by SEQ ID NO:
• 1 and SEQ ID NO:
• 3 and coding for an heparin-glucosamine 3-O-sulfotransferase, and/or
• at least one translation product of said genes, said products being set forth respectively by SEQ ID NO:
• 2 and 4, and comparing said level and/or activity obtained in said sample with the one obtained with a control representing a known disease or health status.

A method for an in vitro screening for a modulator of neurodegenerative diseases, advantageously a Tauopathy, in particular Alzheimer's disease, provided that said neurodegenerative disease is different from a prion disease, comprising:

• a) contacting a sample of a biological fluid previously collected from an animal, in particular a mammal, being subject to a neurodegenerative disease, with a compound to test,
• b) determining the activity and/or a level of:
• i. at least one gene selected from the group consisting of the nucleotidic sequences set forth by SEQ ID NO:
• 1 and SEQ ID NO:
• 3 and coding for an heparin-glucosamine 3-O-sulfotransferase, and/or
• ii. at least one transcription product of a gene selected from the group consisting of the nucleotidic sequences set forth by SEQ ID NO:
• 1 and SEQ ID NO:
• 3 and coding for an heparin-glucosamine 3-O-sulfotransferase, and/or
• iii. at least one translation product of said genes, said products being set forth respectively by SEQ ID NO:
• 2 and 4, and/or
• iv. a fragment or derivative or variant of said gene or transcription or translation product, and/or
• v. heparan sulfate, in particular the level of 3-O-sulfated heparan sulfate, notably the level of 3-O-sulfated heparan sulfate disaccharide
• vi. abnormal phosphorylation of the Tau protein and/or total Tau protein,
• c) determining said activity and/or a level in a control sample of a biological fluid previously collected from a mammal with a neurodegenerative disease not contacted with said compound,
• d) comparing the difference of said activity and/or a level in the contacted sample of a biological fluid with the one in the non contacted sample of a biological fluid, wherein an alteration in said activity and/or level of the contacted cell indicates that the test compound is a modulator of said disease,
• provided that when said activity and/or the level determined in step b) is the one of:
• heparan sulfate, or
• of abnormal phosphorylation of the Tau protein and/or total Tau protein,
• therefore, the activities and/or levels heparan sulfate and abnormal phosphorylation of the Tau protein and/or total Tau protein are both determined, or
• the activity and/or the level of at least one other element chosen among said gene, said transcription product of said genes, said translation product of said genes, or said fragment or derivative or variant of said gene or said transcription or translation product is also determined.